TP53 overexpression is an independent adverse prognostic factor in de novo myelodysplastic syndromes with fibrosis

Bone marrow (BM) fibrosis is associated with poor prognosis in patients with de novo myelodysplastic syndromes (MDS). TP53 mutations and TP53 (p53) overexpression in MDS are also associated with poor patient outcomes. The prevalence and significance of TP53 mutations and TP53 overexpression in MDS with fibrosis are unknown. We studied 67 patients with de novo MDS demonstrating moderate to severe reticulin fibrosis (MDS‐F). Expression of TP53 was evaluated in BM core biopsy specimens using dual‐colour CD34/TP53 immunohistochemistry with computer‐assisted image analysis. Mutation analysis was performed using next‐generation sequencing, or Sanger sequencing methods. TP53 mutations were present in 47·1% of cases. TP53 mutation was significantly associated with TP53 expression (P = 0·0294). High levels of TP53 expression (3 +  in ≥10% cells) were associated with higher BM blast counts (P = 0·0149); alterations of chromosomes 5 (P = 0·0009) or 7 (P = 0·0141); complex karyotype (P = 0·0002); high‐ and very‐high risk IPSS‐R groups (P = 0·009); and TP53 mutations (P = 0·0003). High TP53 expression independently predicted shorter overall survival (OS) by multivariate analysis (P = <0·001). Expression of TP53 by CD34‐positive cells was associated with shorter OS and leukaemia‐free survival (P = 0·0428). TP53 overexpression is a predictor of poor outcome in patients with MDS‐F.     

The enigmas of the lupus anticoagulant: Mechanisms,diagnosis, and management

Lupus anticoagulant (LA) is a laboratory abnormality associated with the antiphospholipid syndrome. It is a paradoxical phenomenon in which one or more in vitro diagnostic clotting tests are prolonged and thus seem due to an anticoagulant, whereas the antiphospholipid syndrome is manifest clinically as inappropriate or excessive thrombosis. LA should be suspected when thrombosis, recurrent fetal loss, or a prolonged phospholipid (PL)-dependent clotting test is present without other identifiable causes. Despite the heterogeneity of LA antibodies, a consensus has evolved to identify the LA. Four conditions must be met for this laboratory diagnosis: 1) prolongation of a PL-based clotting test, 2) confirmation of an inhibitor-like pattern in the clotting test, 3) confirmation of PL dependence in coagulation tests, and 4) exclusion of a specific factor inhibitor. Even with an extensive armamentarium for LA diagnosis and treatment, it is still a formidable task.     

The early achievement of measurable residual disease negativity in the treatment of adults with Philadelphia-negative B-cell acute lymphoblastic leukemia is a strong predictor for survival

The minimal or measurable residual disease (MRD) status following induction/consolidation chemotherapy is an important prognostic endpoint in adult patients with newly diagnosed acute lymphoblastic leukemia (ALL). However, the optimal time-point (TP) of MRD assessment and its impact on outcome remains unclear. We analyzed 215 patients with newly diagnosed Philadelphia negative B-cell ALL who received intensive chemotherapy, and had available MRD assessment by multicolor flow cytometry at two separate TPs. The median time to first TP (1TP) and second TP (2TP) were 24 and 110 days, respectively. At 1TP, 148 patients (68%) were MRD negative and 67 (32%) were positive. Of the 148 patients with negative MRD at 1TP, 147 (99%) maintained it through 2TP. Patients who were MRD negative at both TPs, early MRD responders, had the 3-year event-free survival (EFS), and overall survival (OS) rates of 65% and 76%, respectively. Patients with improved MRD status from positive to negative, late MRD responders, had lower 3-year EFS and OS rates, 42% and 58%, respectively (P = .001). Multivariate analysis showed that KMT2A (MLL) rearrangement and MRD positivity at 1TP were the only factors correlated with worse OS. In conclusion, the earlier achievement of MRD negative remission is a stronger prognostic factor for survival.     

Comparison of Mineral Trioxide Aggregate's Composition with Portland Cements and a New Endodontic Cement

The aim of this study was to compare the compositions of mineral trioxide aggregates (MTAs), Portland cements (PCs), and a new endodontic cement (NEC). Our study also investigated the surface characteristics of MTA and NEC root-end fillings when immersed in normal saline. For part I, we prepared samples of 9 brands of MTAs, PCs, and NEC. The materials were imaged and analyzed by scanning electron microscopy (SEM) and energy dispersive x-ray analysis (EDXA). In part II, 3-mm-deep root-end preparations were filled with MTA or NEC and stored in normal saline for 1 week. Samples were imaged and analyzed by SEM and electron probe microanalysis (EPMA). EDXA investigations revealed differences in the dominant compounds of NEC, PCs, and MTAs. The major components of MTA and PC are the same except for bismuth. The most significant difference was the presence of higher concentrations of Fe (minor element) in gray MTA and PC when compared with white ones. EPMA results revealed remarkably different elements in MTA compared with surrounding dentin, whereas in the NEC group the distribution patterns of calcium, phosphorous, and oxygen were comparable. NEC differs chemically from MTAs and PCs and demonstrates comparable surface composition with adjacent dentin as a root-end filling material.     

The properties of a new endodontic material

The purpose of this study was to analyze the physical properties and chemical compositions of a new experimental cement (NEC) and compare them with mineral trioxide aggregate (MTA); pH, working time, setting time, dimensional changes following setting, flow, film thickness, and chemical composition of NEC and MTA were assessed. For chemical compositions, all specimens were imaged and analyzed by scanning electron microscopy and electron probe microanalysis (EPMA). The physical properties were performed according to ISO 6876:2001. Working time, pH, and dimensional changes of NEC and MTA showed similar results. Shorter setting time was obtained with the NEC compared with MTA (p < 0.05). The NEC showed more flow than MTA. In addition, the film thickness of the NEC was considerably less than the MTA (p < 0.01 and p < 0.001, respectively). EPMA investigations indicated that lime (CaO) was the dominant compound in NEC and MTA; however, other compounds were significantly different. It was concluded that the chemical composition of NEC is different compare with MTA; it can be concluded that the NEC exhibits acceptable physical properties.     

Myeloid neoplasms with concurrent BCR‐ABL1 and CBFB rearrangements: A series of 10 cases of a clinically aggressive neoplasm

Chronic myeloid leukemia (CML) is defined by the presence of t(9;22)(q34;q11.2)/BCR‐ABL1. Additional chromosomal abnormalities confer an adverse prognosis and are particularly common in the blast phase of CML (CML‐BP). CBFB rearrangement, particularly CBFB‐MYH11 fusion resulting from inv(16)(p13.1q22) or t(16;16)(p13.1;q22), is an acute myeloid leukemia (AML)‐defining alteration that is associated with a favorable outcome. The co‐occurrence of BCR‐ABL1 and CBFB rearrangement is extremely rare, and the significance of this finding remains unclear. We identified 10 patients with myeloid neoplasms harboring BCR‐ABL1 and CBFB rearrangement. The study group included six men and four women with a median age of 51 years (range, 20‐71 years). The sequence of molecular alterations could be determined in nine cases: BCR‐ABL1 preceded CBFB rearrangement in seven, CBFB rearrangement preceded BCR‐ABL1 in one, and both alterations were discovered simultaneously in one patient. BCR‐ABL1 encoded for p210 kD in all cases in which BCR‐ABL1 preceded CBFB rearrangement; a p190 kD was identified in the other three cases. Two patients were treated with the FLAG‐IDA regimen (fludarabine, cytarabine, idarubicin, and G‐CSF) and tyrosine kinase inhibitors (TKI); seven with other cytarabine‐based regimens and TKIs, and one with ponatinib alone. At last follow up (median, 16 months; range 2‐85), 7 of 10 patients had died. The co‐existence of BCR‐ABL1 and CBFB rearrangement is associated with poor outcome and a clinical course similar to that of CML‐BP, and unlike de novo AML with CBFB rearrangement, suggesting that high‐intensity chemotherapy with TKI should be considered in these patients.