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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.

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.

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.

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.

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.

Background:Very early rebleeding is frequently encountered in patients with acute oesophageal variceal bleeding. A trial was designed to assess the efficacy and safety in patients with no active bleeding at endoscopy, receiving banding ligation association with terlipressin to prevent very early rebleeding.Methods:Patients with no active variceal bleeding at endoscopy were evaluated. Eligible patients were randomised to receive terlipressin infusion alone for 5 days (Terlipressin group) or banding ligation plus terlipressin infusion for 2 days (Combined group). Primary endpoints were treatment failure and very early rebleeding.Results:The terlipressin group was composed of 46 patients and the Combined group was composed of 47 patients. Both groups were comparable in terms of baseline data. Forty-eight-hour haemostasis was achieved in 91% in the Terlipressin group and 98% in the Combined group (p = 0.20). Very early rebleeding within 48–120 h occurred in 7 patients (15%) in the Terlipressin group but not in any patients (0%) in the Combined group (p = 0.006). Treatment failure was 24% in the Terlipressin group and 2% in the Combined group (p = 0.002). Multivariate analysis revealed that treatment (OR 0.081; 95% CI 0.010 to 0.627) was the only predictive factor of very early rebleeding. Blood requirement was significantly lower in the Combined group than in the Terlipressin group. Complications and 6-week survival were similar in both groups.Conclusions:Combination of banding ligation and terlipressin infusion for 2 days was superior to only infusion of terlipressin for 5 days in the reduction of very early rebleeding and treatment failure in patients with inactive variceal bleeding at endoscopy.Trial registration number:ISRCTN28353453

Recently, mutations of the additional sex comb-like 1 ( ASXL1 ) gene were identified in patients with myelodysplastic syndrome (MDS), but the interaction of this mutation with other genetic alterations and its dynamic changes during disease progression remain to be determined. In this study, ASXL1 mutations were identified in 106 (22.7%) of the 466 patients with primary MDS based on the French-American-British (FAB) classification and 62 (17.1%) of the 362 patients based on the World Health Organization (WHO) classification. ASXL1 mutation was closely associated with trisomy 8 and mutations of RUNX1 , EZH2 , IDH , NRAS , JAK2 , SETBP1 and SRSF2, but was negatively associated with SF3B1 mutation. Most ASXL1- mutated patients (85%) had concurrent other gene mutations at diagnosis. ASXL1 mutation was an independent poor prognostic factor for survival. Sequential studies showed that the original ASXL1 mutation remained unchanged at disease progression in all 32 ASXL1- mutated patients but were frequently accompanied with acquisition of mutations of other genes, including RUNX1 , NRAS, KRAS, SF3B1 , SETBP1 and chromosomal evolution. On the other side, among the 80 ASXL1- wild patients, only one acquired ASXL1 mutation at leukemia transformation. In conclusion, ASXL1 mutations in association with other genetic alterations may have a role in the development of MDS but contribute little to disease progression.

All bacterial isolates from 7058 patients admitted to haemato-oncology wards at National Taiwan University Hospital between 2002 and 2006 were characterized. In total 1307 non-duplicate bloodstream isolates were made from all patients with haematological malignancy; 853 (65%) of these were from neutropenic patients. Gram-negative bacteria predominated (60%) in neutropenic isolates with Escherichia coli (12%), Klebsiella pneumoniae (10%), Acinetobacter calcoaceticus-baumannii complex (6%), and Stenotrophomonas maltophilia (6%) the most frequent. Coagulase-negative staphylococci (19%) and Staphylococcus aureus (4%) were the most common Gram-positive pathogens. Resistance to ciprofloxacin was found in 50% of E. coli and 20% of K. pneumoniae isolates from neutropenic patients. Extensively drug-resistant A. calcoaceticus-baumannii complex and vancomycin-resistant enterococci were also found during the study period. Emerging antimicrobial resistant pathogens are an increasing threat to neutropenic cancer patients.

The effect of porosity––a common welding defect––on the fatigue crack growth rate (FCGR) in Ti–6Al–4V laser welds was investigated. The experimental results reveal that porosity was present in partial penetration welds over a narrow fusion zone (FZ) with martensite structure. The FCGR of the FZ was lower than that of the base plate. The fracture surface morphology of weld metal was much rougher as compared to that of the base plate. Randomly oriented martensite in the FZ led to local cleavage fracture along a preferred plane, thus, altering the crack growth direction significantly out of the primary crack plane. The zigzag crack path in the FZ resulted in a reduced FCGR at a given ΔK compared to the base plate. Besides, the porous weld showed a serration on the crack growth curve, and behaved the similar crack growth characteristics as the defect free one. SEM fractography revealed that the deflection of crack path around porosity together with local notch blunting as the crack tip pierced into porosity, balanced the increased FCGR for the occurrence of instant crack advance as the crack front reached the porosity at a low stress ratio. In contrast, the serration and drop in FCGR occurred sparingly at a high stress ratio as the crack front met the porosity.

To explore the validity and prognostic significance of minimal residual disease detection by quantitative polymerase chain reaction (qPCR) in patients of acute myeloid leukemia (AML) bearing Nucleophosmin (NPM1) mutations, we quantified mutants in 194 bone marrow samples from 38 patients with a median follow-up time of 20.6 months. Following induction chemotherapy, a median of 2.78 log decline in mutant copy number was observed. Relapse was always accompanied by significant increase of mutant numbers (P<0.001). After achieving complete remission (CR), the mutant copy number was significantly higher in patients with subsequent relapse than in those remaining in continuous CR (P<0.001). Presence of detectable mutants after treatment predicted relapse if no further chemotherapy was administered. Furthermore, the patients with any rise of mutant signals during serial follow-up had 3.2-fold increase of relapse risk compared to those with persistently low or undetectable signals (P<0.001). Patients who could achieve mutant reduction to <0.1% of internal control had significantly longer overall survival (OS) (P=0.004) and relapse-free survival (RFS) (P<0.001). Failure to achieve 2 logs of reduction after consolidation predicted shorter OS (P=0.01) and RFS (P=0.001). In conclusion, qPCR monitoring may have prognostic impact in AML patients with NPM1 mutations.