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Obinutuzumab is an anti-CD20 antibody engineered to elicit killing mechanisms distinct from rituximab. In a trial of chemotherapy plus obinutuzumab or rituximab that used the antibody as maintenance therapy for 2 years, obinutuzumab prolonged progression-free survival.

Patients with paroxysmal nocturnal hemoglobinuria who had a poor response to eculizumab therapy were found to have a genetic polymorphism in C5 that prevents binding by the antibody. Paroxysmal nocturnal hemoglobinuria (PNH) arises as a consequence of clonal expansion of hematopoietic stem cells that have acquired a somatic mutation in the gene encoding phosphatidylinositol glycan anchor biosynthesis class A ( PIGA ). 1 – 3 The resulting hematopoietic cells are deficient in glycosylphosphatidylinositol-anchored proteins, including the complement regulatory proteins CD55 and CD59; this accounts for the intravascular hemolysis that is the primary clinical manifestation of PNH. 4 – 6 PNH frequently develops in association with disorders involving bone marrow failure, particularly aplastic anemia. Thrombosis is a major cause of PNH-associated morbidity and mortality, particularly among white patients. 7 – 9 Eculizumab (Soliris, Alexion Pharmaceuticals) . . .

In classical Hodgkin lymphoma (cHL)—characterized by the presence of Hodgkin and Reed-Sternberg (HRS) cells—tumor-associated macrophages (TAMs) play a pivotal role in tumor formation. However, the significance of direct contact between HRS cells and TAMs has not been elucidated. HRS cells and TAMs are known to express PD-L1, which leads to PD-1+ CD4+ T cell exhaustion in cHL. Here, we found that PD-L1/L2 expression was elevated in monocytes co-cultured with HRS cells within 1 h, but not in monocytes cultured with supernatants of HRS cells. Immunofluorescence analysis of PD-L1/L2 revealed that their upregulation resulted in membrane transfer called “trogocytosis” from HRS cells to monocytes. PD-L1/L2 upregulation was not observed in monocytes co-cultured with PD-L1/L2-deficient HRS cells, validating the hypothesis that there is a direct transfer of PD-L1/L2 from HRS cells to monocytes. In the patients, both ligands (PD-L1/L2) were upregulated in TAMs in contact with HRS cells, but not in TAMs distant from HRS cells, suggesting that trogocytosis occurs in cHL patients. Taken together, trogocytosis may be one of the mechanisms that induces rapid upregulation of PD-L1/L2 in monocytes to evade antitumor immunity through the suppression of T cells as mediated by MHC antigen presentation.

Tazemetostat is a selective, reversible, small‐molecule inhibitor of the histone methyltransferase enzyme, enhancer of zest homolog 2 (EZH2). In this multicenter, open‐label, phase II study, we assessed the efficacy and safety of tazemetostat in Japanese patients with relapsed or refractory (R/R) B‐cell non‐Hodgkin lymphoma harboring the EZH2 mutation. Tazemetostat (800 mg twice daily) was given orally (28‐day cycle) until disease progression or unacceptable toxicity. Among the 20 eligible patients, 17 were enrolled in cohort 1 (follicular lymphoma [FL]), and three were enrolled in cohort 2 (diffuse large B‐cell lymphoma). At data cut‐off, the objective response rate in cohort 1 was 76.5%, including six patients (35.3%) with complete response and seven patients (41.2%) with partial response (PR). All three patients in cohort 2 achieved PR. In cohort 1, median progression‐free survival (PFS) was not reached at the median follow‐up of 12.9 months. The estimated PFS rate at 12 and 15 months was 94.1% and 73.2%, respectively. The most common grade 3 treatment‐emergent adverse event (TEAE) was lymphopenia (n = 2). Grade 4 TEAEs included hypertriglyceridemia and pneumonia aspiration (n = 1 each), which were not related to tazemetostat. Treatment‐emergent adverse events leading to study drug discontinuation were reported in four of the 20 patients, indicating that the safety profile of tazemetostat was acceptable and manageable. Tazemetostat 800 mg twice daily showed encouraging efficacy in patients with R/R EZH2 mutation‐positive FL with a manageable safety profile in the overall population. Thus, tazemetostat could be a potential treatment for R/R EZH2 mutation‐positive FL. Percentage change from baseline in sum of the product of the perpendicular diameters of target lesions based on independent reviewer assessment.

Let G be a 3-connected graph. An edge (a triangle) of G is said to be a 3-contractible edge (a 3-contractible triangle) if the contraction of it results in a 3-connected graph. We denote by E c ( G ) and T c ( G ) the set of 3-contractible edges of G and the set of 3-contractible triangles of G , respectively. We prove that if | V ( G ) | ≥ 7 , then | E c ( G ) | + 15 14 | T c ( G ) | ≥ 6 7 | V ( G ) | . We also determine the extremal graphs.

Pregnancy-associated primary red cell aplasia (pPRCA) is a rare disorder that may occur at various time points during pregnancy. Unlike pregnancy-associated aplastic anemia, pPRCA is usually reversible, and no maternal deaths attributable to pPRCA have been reported. Herein, we report a woman diagnosed with pPRCA in two consecutive pregnancies. Corticosteroids were found to be ineffective, and she required a large number of red blood cell transfusions during both pregnancies. Despite severe anemia developing in both pregnancies, two healthy babies were vaginally born and spontaneous remission of pPRCA was seen after delivery. Interestingly, in both events of pPRCA described here, a transient rise of reticulocytes was observed precedent to the authentic recovery phase of reticulocytes and remission of pPRCA, which is a novel finding that has not been reported. The significance of this phenomenon has yet to be elucidated. Along with this case report, we review all 15 cases with 21 events of pPRCA in the literature, including the present case.

This multicenter, prospective phase IIb trial evaluating the efficacy and safety of tucidinostat (HBI‐8000) in patients with relapsed or refractory (R/R) adult T‐cell leukemia/lymphoma (ATLL) was undertaken in Japan. Eligible patients had R/R ATLL and had failed standard of care treatment with chemotherapy and with mogamulizumab. Twenty‐three patients received tucidinostat 40 mg orally twice per week and were included in efficacy and safety analyses. The primary end‐point was objective response rate (ORR) assessed by an independent committee. The ORR was 30.4% (95% confidence interval [CI], 13.2, 52.9]. Median progression‐free survival was 1.7 months (95% CI, 0.8, 7.4), median duration of response was 9.2 months (95% CI, 2.6, not reached), and median overall survival was 7.9 months (95% CI, 2.3, 18.0). All patients experienced adverse events (AEs), which were predominantly hematologic and gastrointestinal. Incidence of grade 3 or higher AEs was 78.3%; most were laboratory abnormalities (decreases in platelets, neutrophils, white blood cells, and hemoglobin). Tucidinostat was well tolerated with AEs that could be mostly managed with supportive care and dose modifications. Tucidinostat is a meaningful treatment option for R/R ATLL patients; further investigation is warranted. Tucidinostat is an oral novel benzamide HDACi of HDAC isoenzymes 1, 2, 3 and 10 selectively. 23 patients with relapsed/refractory ATLL were treated with tucidinostat 40mg orally twice a week. Out of 23 patients, 7 showed objective responses including 1 CR, and ORR was 30.4%.

The relationship between fetal hemoglobin (HbF) levels and disease prognosis in patients with myelodysplastic syndrome (MDS) is unclear. This study aimed to clarify the relationship between HbF level and the prognosis of MDS. To this end, data from 217 patients diagnosed with MDS between April 2006 and August 2020 at Ebina General Hospital were analyzed retrospectively. The primary endpoint was leukemia-free survival (LFS) for 5 years after diagnosis. HbF levels were significantly higher in patients with MDS than in control patients without MDS ( n  = 155), with a cut-off value of 0.4%. Higher-risk patients had a similar prognosis regardless of HbF level, but lower-risk patients had longer LFS at intermediate HbF levels. Although prognosis based on pre-treatment HbF levels did not differ significantly among azacitidine-treated patients, prognosis tended to be better in lower-risk patients with intermediate HbF levels. Multivariate analysis showed that the intermediate HbF category correlated with LFS, independently of MDS lower-risk prognostic scoring system (LR-PSS)-related factors. This study is the first to assess the association between HbF levels and the new World Health Organization 2016 criteria for MDS, demonstrating the significance of HbF levels in the prognosis of MDS.

Tumor‐associated macrophages (TAMs) are associated with a poor prognosis of diffuse large B‐cell lymphoma (DLBCL). As macrophages are heterogeneous, the immune polarization and their pathological role warrant further study. We characterized the microenvironment of DLBCL by immunohistochemistry in a training set of 132 cases, which included 10 Epstein–Barr virus‐encoded small RNA (EBER)‐positive and five high‐grade B‐cell lymphomas, with gene expression profiling in a representative subset of 37 cases. Diffuse large B‐cell lymphoma had a differential infiltration of TAMs. The high infiltration of CD68 (pan‐macrophages), CD16 (M1‐like), CD163, pentraxin 3 (PTX3), and interleukin (IL)‐10‐positive macrophages (M2c‐like) and low infiltration of FOXP3‐positive regulatory T lymphocytes (Tregs) correlated with poor survival. Activated B cell‐like DLBCL was associated with high CD16, CD163, PTX3, and IL‐10, and EBER‐positive DLBCL with high CD163 and PTX3. Programmed cell death‐ligand 1 positively correlated with CD16, CD163, IL‐10, and RGS1. In a multivariate analysis of overall survival, PTX3 and International Prognostic Index were identified as the most relevant variables. The gene expression analysis showed upregulation of genes involved in innate and adaptive immune responses and macrophage and Toll‐like receptor pathways in high PTX3 cases. The prognostic relevance of PTX3 was confirmed in a validation set of 159 cases. Finally, in a series from Europe and North America (GSE10846, R‐CHOP‐like treatment, n = 233) high gene expression of PTX3 correlated with poor survival, and moderately with CSF1R, CD16, MITF, CD163, MYC, and RGS1. Therefore, the high infiltration of M2c‐like immune regulatory macrophages and low infiltration of FOXP3‐positive Tregs is associated with a poor prognosis in DLBCL, for which PTX3 is a new prognostic biomarker. This research focused on the analysis of several macrophage and regulatory T lymphocyte markers in diffuse large b‐cell lymphoma. We found that high PTX3 expression correlated with poor prognosis of the patients.

RAS/RAF/MEK/ERK pathway inhibitors exhibit significant anti-tumor effects against various tumor types, including multiple myeloma (MM), and they are predicted to play a pivotal role in precision medicine. The XPO1 inhibitor KPT-330 has also exhibited promising efficacy in combination with other novel drugs in treating relapsed/refractory MM (RRMM). In this study, we explored the anti-tumor effects of a combination of the pan-RAF inhibitor TAK-580 and KPT-330. Importantly, TAK-580 enhanced KPT-330-induced cytotoxicity and apoptosis in human myeloma cell lines and primary myeloma cells from RRMM patients. Moreover, TAK-580 and KPT-330 synergistically inhibited nuclear phospho-FOXO3a and enhanced cytoplasmic phospho-FOXO3a in MM cells, leading to cytoplasmic enhanced Bim expression and finally apoptosis. This indicates that TAK-580 enhances KPT-330-induced cytotoxicity and apoptosis primarily via the FOXO3a–Bim axis. In addition, TAK-580 enhanced the cytotoxicity of KPT-330 against MM cells even in the presence of IGF-1. Taken together, our results demonstrate that a combination of pan-RAF inhibitor and XPO1 inhibitor is a potential therapeutic option in treating MM.