A number of patient-specific and leukemia-associated factors are related to the poor outcome in older patients with acute myeloid leukemia (AML). However, comprehensive studies regarding the impact ...of genetic alterations in this group of patients are limited. In this study, we compared relevant mutations in 21 genes between AML patients aged 60 years or older and those younger and exposed their prognostic implications. Compared with the younger patients, the elderly had significantly higher incidences of PTPN11, NPM1, RUNX1, ASXL1, TET2, DNMT3A and TP53 mutations but a lower frequency of WT1 mutations. The older patients more frequently harbored one or more adverse genetic alterations. Multivariate analysis showed that DNMT3A and TP53 mutations were independent poor prognostic factors among the elderly, while NPM1 mutation in the absence of FLT3/ITD was an independent favorable prognostic factor. Furthermore, the status of mutations could well stratify older patients with intermediate-risk cytogenetics into three risk groups. In conclusion, older AML patients showed distinct genetic alterations from the younger group. Integration of cytogenetics and molecular mutations can better risk-stratify older AML patients. Development of novel therapies is needed to improve the outcome of older patients with poor prognosis under current treatment modalities.
The TP53 mutation is frequently detected in acute myeloid leukemia (AML) patients with complex karyotype (CK), but the stability of this mutation during the clinical course remains unclear. In this ...study, TP53 mutations were identified in 7% of 500 patients with de novo AML and 58.8% of patients with CK. TP53 mutations were closely associated with older age, lower white blood cell (WBC) and platelet counts, FAB M6 subtype, unfavorable-risk cytogenetics and CK, but negatively associated with NPM1 mutation, FLT3/ITD and DNMT3A mutation. Multivariate analysis demonstrated that TP53 mutation was an independent poor prognostic factor for overall survival and disease-free survival among the total cohort and the subgroup of patients with CK. A scoring system incorporating TP53 mutation and nine other prognostic factors, including age, WBC counts, cytogenetics and gene mutations, into survival analysis proved to be very useful to stratify AML patients. Sequential study of 420 samples showed that TP53 mutations were stable during AML evolution, whereas the mutation was acquired only in 1 of the 126 TP53 wild-type patients when therapy-related AML originated from different clone emerged. In conclusion, TP53 mutations are associated with distinct clinic-biological features and poor prognosis in de novo AML patients and are rather stable during disease progression.
Notched tensile tests were conducted under a slow displacement rate to evaluate the influences of grain size and aging on hydrogen embrittlement (HE) of T-200 maraging steel. In addition, an ...electrochemical permeation method was employed to measure the effective diffusivity (
D
eff) and apparent solubility (
C
app) for hydrogen of various heat-treated specimens. The results indicated that the aged (482
°C/4
h) specimens comprised of numerous precipitates led to a raised
C
app and a decreased hydrogen diffusivity as compared to those of the solution-treated ones. The solution-treated specimens were resistant to gaseous HE, whereas aged specimens were susceptible to it, implying the strength level was the controlling factor to affect the HE susceptibility of the specimens. Nevertheless, all specimens suffered from sulfide stress corrosion cracking (SSCC) severely but to different degrees. The aged specimens were more likely to form intergranular (IG) fractures in H
2S but quasi-cleavage (QC) in H
2. For the solution-treated specimens, a fine-grained structure was susceptible to HE in H
2S and revealed mainly QC that differed from the IG fracture of the coarse-grained one. The fracture mode of the specimens could also be related to the transport path and / or the supply of hydrogen to the plastic zone of notched specimens in hydrogen-containing environments.
► Sulfide cracking of rolled AISI 304L in distinct conditions was conducted. ► Hydrogen embrittlement (HE) caused obviously localized deformation. ► Rolling at room temperature caused a reduced HE ...susceptibility in tensile tests. ► The WR specimen had better resistance to HE in notched tensile and U bent tests. ► The CR specimen was susceptible to sulfide cracking in the U-bent immersion test.
The effects of rolling temperature (25 and 150°C) and sensitization treatment (650°C/1h) on the susceptibility to sulfide stress corrosion cracking of 304L specimens were investigated. Regardless of the rolling temperature, the low hydrogen embrittlement (HE) susceptibility was associated with a high α′-martensite content and/or deformability near the notch-fractured location. In contrast, sensitization treatment increased the HE susceptibility of all rolled specimens. Additionally, cracks were observed only on the cold-rolled specimen in the U-bend immersion tests. The superior performance of the warm-rolled specimen in saturated H2S solution was confirmed by both notched tensile and U-bend immersion tests.
Although the clinical features of the Isocitrate dehydrogenase 2 (IDH2) mutation in acute myeloid leukemia (AML) have been characterized, its prognostic significance remains controversial and its ...stability has not been investigated. We analyzed 446 adults with primary non-M3 AML and found IDH2 R172, R140 and IDH1 R132 mutations occurred at a frequency of 2.9, 9.2 and 6.1%, respectively. Compared with wild-type IDH2, mutation of IDH2 was associated with higher platelet counts, intermediate-risk or normal karyotype and isolated +8, but was inversely correlated with expression of HLA-DR, CD34, CD15, CD7 and CD56, and was mutually exclusive with WT1 mutation and chromosomal translocations involving core-binding factors. All these correlations became stronger when IDH1 and IDH2 mutations were considered together. Multivariate analysis revealed IDH2 mutation as an independent favorable prognostic factor. IDH2(-)/FLT3-ITD(+) genotype conferred especially negative impact on survival. Compared with IDH2 R140 mutation, IDH2 R172 mutation was associated with younger age, lower white blood cell count and lactate dehydrogenase level, and was mutually exclusive with NPM1 mutation. Serial analyses of IDH2 mutations at both diagnosis and relapse in 121 patients confirmed high stability of IDH2 mutations. In conclusion, IDH2 mutation is a stable marker during disease evolution and confers favorable prognosis.
This paper proposes a pairwise likelihood estimator based on an analytic approximation method for the random effects probit model. It is widely known that the standard approach for the random effects ...probit model relies on numerical integration and that its likelihood function does not have a closed form. When the number of time periods or the serial correlation across periods is large, the resulting estimator is likely to become biased. This study derives an analytic approximation for the likelihood function of one pair of time periods without relying on typical numerical-integral procedures. We then apply this formula in a pairwise likelihood estimation procedure to derive our estimator, which is obtained as the product of the analytic approximation of the likelihood function for all possible pairs of time periods. A simulation study is conducted for the comparison of our proposed estimator with the estimators for the pooled probit model and Gaussian quadrature procedure. The evidence shows that our proposed estimator enjoys desirable asymptotic properties. In addition, compared to the estimator based on the Gaussian quadrature procedure, our proposed estimator exhibits comparable performances in all the configurations considered in the simulation study and shows superiority for the cases of a large number of time periods and high serial correlation across periods. We apply our proposed estimator to British Household Panel Survey data so as to characterize the trend of working probabilities.
Conventionally, acute myeloid leukemia (AML) patients are categorized into good-, intermediate- and poor-risk groups according to cytogenetic changes. However, patients with intermediate-risk ...cytogenetics represent a largely heterogeneous population regarding treatment response and clinical outcome. In this study, we integrated cytogenetics and molecular mutations in the analysis of 318 patients with de novo non-M3 AML who received standard chemotherapy. According to the mutation status of eight genes, including NPM1, CEBPA, IDH2, RUNX1, WT1, ASXL1, DNMT3A and FLT3, that had prognostic significance, 229 patients with intermediate-risk cytogenetics could be refinedly stratified into three groups with distinct prognosis (P<0.001); patients with good-risk genotypes had a favorable outcome (overall survival, OS, not reached) similar to those with good-risk cytogenetics, whereas those with poor-risk genotypes had an unfavorable prognosis (OS, 10 months) similar to those with poor-risk cytogenetics (OS, 13.5 months), and the remaining patients with other genotypes had an intermediate outcome (OS, 25 months). Integration of cytogenetic and molecular profiling could thus reduce the number of intermediate-risk AML patients from around three-fourth to one-fourth. In conclusion, integration of cytogenetic and molecular changes improves the prognostic stratification of AML patients, especially those with intermediate-risk cytogenetics, and may lead to better decision on therapeutic strategy.
Introduction
Surgery in patients with haemophilia B carries a high risk of excessive bleeding and requires adequate haemostatic control until wound healing. Nonacog beta pegol, a long‐acting ...recombinant glycoPEGylated factor IX (FIX), was used in the perioperative management of patients undergoing major surgery.
Aim
To evaluate the efficacy and safety of nonacog beta pegol in patients with haemophilia B who undergo major surgery.
Methods
This was an open‐label, multicentre, non‐controlled surgery trial aimed at assessing peri‐ and postoperative efficacy and safety of nonacog beta pegol in 13 previously treated patients with haemophilia B. All patients received a preoperative nonacog beta pegol bolus injection of 80 IU kg−1. Postoperatively, the patients received fixed nonacog beta pegol doses of 40 IU kg−1, repeated at the investigator's discretion. Safety assessments included monitoring of immunogenicity and adverse events.
Results
Intraoperative haemostatic effect was rated ‘excellent’ or ‘good’ in all 13 cases. Apart from the preoperative injection, none of the patients needed additional doses of nonacog beta pegol on the day of surgery. The median number of postoperative doses of nonacog beta pegol was 2.0 from days 1 to 6 and 1.5 from days 7 to 13. No unexpected intra‐ or postoperative complications were observed including deaths or thromboembolic events. No patients developed inhibitors.
Conclusions
These results indicated that nonacog beta pegol was safe and effective in the perioperative setting, allowing major surgical interventions in patients with haemophilia B with minimal peri‐ and postoperative concentrate consumption and infrequent injections as reported with standard FIX products.
This work investigated the effect of microstructure on the susceptibility of 304L (metastable), 310S (stable) austenitic and 410 martensitic stainless steels (SSs) to hydrogen embrittlement (HE). ...Slow-displacement-rate notched tensile tests were performed at various combinations of temperature (25 and 80°C) and environment (air and H2) to evaluate the relative HE susceptibility of these alloys. At 25°C, the untempered 410 SS was the specimen most susceptible to HE among the investigated specimens, whereas the 310S and tempered 410 specimens exhibited low HE susceptibility. The formation of strain-induced α′-martensite in a localized region in front of the notch tip was the main cause for the high HE susceptibility of the 304L SS tested at 25°C. In general, the HE susceptibility was reduced to various degrees for specimens tested at 80°C. A significantly lower susceptibility to HE was observed for the 304L specimen at 80°C due to the suppressed formation of α′-martensite in the highly strained region.
•The oxidation of three high-entropy alloys was studied in dry air at 700–900°C.•The oxidation kinetics of all the alloys followed the parabolic rate law.•Multiple scales formed on the alloys were ...strongly composition-dependent.
The oxidation of three quinary equimolar high-entropy alloys, containing FeCoNiCrAl, FeCoNiCrMn, and FeCoNiCrSi was studied in dry air at 700–900°C. The Mn-containing alloy was single-phase, while both Al- and Si-containing alloys were dual-phase. The oxidation kinetics of all the alloys followed the parabolic rate law, regardless of temperature and alloy composition. The oxidation rates of both Al- and Si-containing alloys were lower than those of the quaternary FeCoNiCr alloy, while those of the Mn-containing alloy went to an opposite direction. Multiple scales formed on the alloys were strongly composition-dependent.
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