Blood Research最新文献

Purpose: This study aimed to determine the frequency of regulatory T cells (Tregs) (CD4⁺/FOXP3⁺) and indoleamine 2,3-dioxygenase (IDO) expression in patients with acute myeloid leukemia (AML).

Methods: This cross-sectional case-control study was conducted between Jan 2022 and Dec 2023. Bone marrow samples were collected from 20 healthy individuals and 15 patients with AML. Flow cytometry, real-time polymerase chain reaction (PCR), and western blotting were used to evaluate the frequency of Treg and IDO expression levels.

Results: The Treg percentage among total lymphocytes was lower in the AML group than that in the normal group. However, Treg percentage among T-helper (Th) lymphocytes was significantly higher in the AML group than that in the normal group (p < 0.05). The mean IDO expression in the AML group was significantly higher than that in the normal group (p = 0.004). A significant relationship was observed between IDO expression and Treg percentage among Th lymphocytes in the AML group (correlation = 0.637; p = 0.003). Moreover, western blot analysis showed a significant increase in IDO protein intensity in the AML group compared with that in the control group (p < 0.001). A significant difference was observed between the IDO concentrations in the AML group and that in the control group (p < 0.001). In addition, a significant difference between TGF-β levels in the AML group and those in the control group (p < 0.01) was observed.

Conclusion: IDO inhibition using novel IDO inhibitors along with chemotherapy is a promising approach to overcome the immune escape mechanisms in patients with AML, who exhibit increased levels of IDO expression and Tregs.

Purpose: The fifth World Health Organization (WHO) classification (2022 WHO) and International Consensus Classification (ICC) of myeloid neoplasms have recently been published. In this study, patients were reclassified according to the revised classification and their prognoses were analyzed to confirm the clinical utility of the new classifications.

Methods: We included 101 adult patients, 77 with acute myeloid leukemia (AML) and 24 with myelodysplastic neoplasms (MDS), who underwent bone marrow aspiration and next-generation sequencing (NGS) between August 2019 and July 2023. We reclassified the patients according to the revised criteria, examined the differences, and analyzed the prognosis using survival analysis.

Results: According to the 2022 WHO and ICC, 23 (29.9%) patients and 32 (41.6%) patients were reclassified into different groups, respectively, due to the addition of myelodysplasia-related (MR) gene mutations to the diagnostic criteria or the addition of new entities associated with TP53 mutations. The median overall survival (OS) of patients with AML and MR gene mutations was shorter than that of patients in other AML groups; however, the difference was not significant. Patients with AML and TP53 mutation had a significantly shorter OS than the other AML group (p = 0.0014, median OS 2.3 vs 10.3 months). They also had significantly shorter OS than the AML and MR mutation group (p = 0.002, median OS 2.3 vs 9.6 months).

Conclusion: The revised classifications allow for a more detailed categorization based on genetic abnormalities, which may be helpful in predicting prognosis. AML with TP53 mutations is a new ICC category that has shown a high prognostic significance in a small number of cases.

The diagnosis of acute ischemic stroke (AIS) can be challenging when neuroimaging findings are normal or equivocal. Neutrophil extracellular traps (NETs), particularly histone H3.1, have potential as biomarkers for AIS. This study evaluated NETs, specifically histone H3.1, as diagnostic biomarkers for AIS. This prospective study included 89 patients with AIS and 20 healthy controls. Plasma histone H3.1 levels were measured using the Nu.Q® H3.1 enzyme-linked immunosorbent assay (ELISA). Seven cytokines were analyzed using a bead-based immunoassay. Statistical analyses were used to compare histone H3.1 levels between groups and evaluate correlations with clinical parameters and cytokines. Histone H3.1 levels were significantly higher in patients with AIS (271.05 ± 33.40 ng/mL) versus controls (95.33 ± 12.86 ng/mL, p < 0.001). Multivariable logistic regression identified H3.1 as an independent risk factor for AIS (p = 0.006), with an area under the curve of 0.907. Significant correlations were found between H3.1, interleukin-6 (0.290, p = 0.013) and vascular cell adhesion molecule 1 (0.297, p = 0.011). In conclusion, the NETs H3.1 ELISA test is a reliable new diagnostic option that supports the diagnosis of AIS.

Understanding the intricacies of the pathophysiology and genomic landscape has enhanced the long-term outcomes for patients with acute myeloid leukemia (AML). The identification of novel molecular targets has introduced new therapeutic strategies that attempt to surpass the dominance of the "7 + 3 regimen" established in the 1970s. In 2022, the World Health Organization and International Consensus Classification revised their definitions and approaches to AML, reflecting the current and evolving changes at the molecular level. The guidelines are now grounded in a definition of the disease that emphasizes genetic characteristics. Today, we recognize AML as a genetically diverse disease; a retrospective study identified 5234 driver mutations across 76 genes or genomic regions, with two or more drivers observed in 86% of patients (Papaemmanuil et al., N Engl J Med 374:2209-21, 2016).

Blood cancers, including leukemia, multiple myeloma, and lymphoma, pose significant challenges owing to their heterogeneous nature and the limitations of traditional treatments. Precision medicine has emerged as a transformative approach that offers tailored therapeutic strategies based on individual patient profiles. Ex vivo drug sensitivity analysis is central to this advancement, which enables testing of patient-derived cancer cells against a panel of therapeutic agents to predict clinical responses. This review provides a comprehensive overview of the latest advancements in ex vivo drug sensitivity analyses and their application in blood cancers. We discuss the development of more comprehensive drug response metrics and the evaluation of drug combinations to identify synergistic interactions. Additionally, we present evaluation of the advanced therapeutics such as antibody-drug conjugates using ex vivo assays. This review describes the critical role of ex vivo drug sensitivity analyses in advancing precision medicine by examining technological innovations and clinical applications. Ultimately, these innovations are paving the way for more effective and individualized treatments, improving patient outcomes, and establishing new standards for the management of blood cancers.

Background: Immunochemotherapy has demonstrated a promising efficacy for a variety of B-cell lymphoma but has limited efficacy for Epstein-Barr virus-positive (EBV +) diffuse large B-cell lymphoma (DLBCL) that is refractory or relapsed to conventional chemotherapy regimens. Considering higher programmed death-ligand 1 (PD-L1) expression in the subset of patients with DLBCL with positive EBV, we speculated that PD-1 inhibitors plus chemotherapy may be an alternative regimen in patients with refractory/relapsed EBV + DLBCL.

Methods: This retrospective study included six adult patients diagnosed with refractory EBV + DLBCL resistant to first-line immunochemotherapy regimens (R-CHOP). These patients received PD-1 inhibitors plus chemotherapy as second-line treatment.

Results: The final analysis included six patients (four men and two women (median age, 50 years; range, 39-83 years)). Four patients were diagnosed with Epstein-Barr virus (EBV) + DLBCL, and two had DLBCL associated with chronic inflammation. Over a median follow-up of 20 months (range, 2-31 months), the objective response rate was 83% (5/6) and the complete remission rate was 67% (4/6). No severe immune-related adverse reactions occurred, and only a mild rash was reported, which did not necessitate the discontinuation of therapy.

Conclusion: The combination of PD-1 inhibitors and chemotherapy offers promising results as a second-line treatment for patients with refractory EBV + DLBCL that is resistant to first-line immunochemotherapy regimens. These preliminary findings warrant further investigation in larger clinical trials to validate the efficacy and safety of this therapeutic approach.

The classic coagulation cascade model of intrinsic and extrinsic coagulation pathways, i.e. contact activation pathway and tissue factor pathway, has been widely modified. The cascade can be categorized as follows: 1) initiation by tissue factor (TF), 2) amplification by the intrinsic tenase complex, and 3) propagation on activated platelets. TF-FVIIa forms an extrinsic tenase complex and activates FX to FXa and FIX to FIXa. FXa-FVa forms a prothrombinase complex that converts prothrombin into thrombin. At this initial stage of coagulation, only small amounts of thrombin are generated owing to the low circulating levels of FVa. The generated thrombin, although in minor quantities, is sufficient to prime the subsequent coagulation reactions. Platelets and in turn FV, FVIII, and FXI are activated. Subsequently, FVIIIa binds to FIXa to form the intrinsic tenase complex, which is aided by a cofactor, FVIIIa, and activates FX at a rate 50-times higher than that of the extrinsic tenase complex, thereby amplifying thrombin generation. Thrombin cleaves fibrinogen into one fibrin monomer and two fibrinopeptides. Fibrin monomers aggregate, crosslink, and branch into an insoluble fibrin network structure. The contact activation system is initiated by FXII, which is activated upon exposure to negatively charged surfaces. Coagulation is driven by FXIIa-mediated FXI cleavage. FXIa activates FIX, which forms an intrinsic tenase complex, eventually leading to thrombin formation. The contact activation system is considered to contribute to thrombosis but is not required for hemostasis in vivo.

Purpose: Hemophilia A is a genetic disorder characterized by a lack of factor VIII (FVIII). Emicizumab, a recombinant humanized bispecific monoclonal antibody, mimics the function of FVIII. In this article, we present data on an initial real-world evaluation of emicizumab use in Korean children with severe hemophilia A without inhibitors.

Methods: This study was conducted from June 2020 to March 2024 at 4 centers in Korea. The participants were pediatric patients with severe hemophilia A without inhibitors who had received emicizumab treatment for over 6 months. The mean and median annualized bleeding rates (ABRs) and mean and median annual joint bleeding rates (AJBRs) were compared.

Results: Each of the 21 patients in the study received an emicizumab loading regimen of 3 mg/kg weekly for 4 weeks, followed by a modified maintenance regimen of which 2 patients (9.5%) received a 1.5 mg/kg weekly dose, 3 patients (14.3%) received a 6 mg/kg dose every 4 weeks, and the remaining 16 patients (76.2%) received a 3 mg/kg dose every 2 weeks. Before emicizumab prophylaxis initiation, the mean and median ABRs for all patients were 7.04 (SD ± 5.83) and 6.52 (range 0-21.74), respectively. After receiving emicizumab treatment, the mean and mediam ABRs decreased to 0.41 and zero, respectively. Additionally, 85.7% of the patients achieved no bleeding events within 6 months of starting the treatment.

Conclusion: These first real-world data in Korea indicate that emicizumab is effective and safe for pediatric patients with severe hemophilia A without inhibitors.

Background: SM-like (LSM) genes a family of RNA-binding proteins, are involved in mRNA regulation and can function as oncogenes by altering mRNA stability. However, their roles in B-cell progression and tumorigenesis remain poorly understood.

Methods: We analyzed gene expression profiles and overall survival data of 123 patients with mantle cell lymphoma (MCL). The LSM index was developed to assess its potential as a prognostic marker of MCL survival.

Results: Five of the eight LSM genes were identified as potential prognostic markers for survival in MCL, with particular emphasis on the LSM.index. The expression levels of these LSM genes demonstrated their potential utility as classifiers of MCL. The LSM.index-high group exhibited both poorer survival rates and lower RNA levels than did the overall transcript profile. Notably, LSM1 and LSM8 were overexpressed in the LSM.index-high group, with LSM1 showing 2.5-fold increase (p < 0.001) and LSM8 depicting 1.8-fold increase (p < 0.01) than those in the LSM.index-low group. Furthermore, elevated LSM gene expression was associated with increased cell division and RNA splicing pathway activity.

Conclusions: The LSM.index demonstrates potential as a prognostic marker for survival in patients with MCL. Elevated expression of LSM genes, particularly LSM1 and LSM8, may be linked to poor survival outcomes through their involvement in cell division and RNA splicing pathways. These findings suggest that LSM genes may contribute to the aggressive behavior of MCL and represent potential targets for therapeutic interventions.