The prognostic significance of early treatment response in pediatric relapsed acute myeloid leukemia: results of the international study Relapsed AML 2001/01

The prognostic significance of early response to treatment has not been reported in relapsed pediatric acute myeloid leukemia. In order to identify an early and easily applicable prognostic factor allowing subsequent treatment modifications, we assessed leukemic blast counts in the bone marrow by morphology on days 15 and 28 after first reinduction in 338 patients of the international Relapsed-AML2001/01 trial. Both day 15 and day 28 status was classified as good (≤20% leukemic blasts) in 77% of patients. The correlation between day 15 and 28 blast percentages was significant, but not strong (Spearman correlation coefficient = 0.49, P<0.001). Survival probability decreased in a stepwise fashion along with rising blast counts at day 28. Patients with bone marrow blast counts at this time-point of ≤5%, 6–10%, 11–20% and >20% had 4-year probabilities of survival of 52%±3% versus 36%±10% versus 21%±9% versus 14%±4%, respectively, P<0.0001; this trend was not seen for day 15 results. Multivariate analysis showed that early treatment response at day 28 had the strongest prognostic significance, superseding even time to relapse (< or ≥12 months). In conclusion, an early response to treatment, measured on day 28, is a strong and independent prognostic factor potentially useful for treatment stratification in pediatric relapsed acute myeloid leukemia. This study was registered with ISRCTN code: 94206677.     

Factor XIII Val34Leu polymorphism and recurrent myocardial infarction in patients with coronary artery disease

Factor XIII (FXIII) is necessary for cross linking of fibrin strands and generation of stable fibrin clot. FXIII Val34Leu is a common genetic single nucleotide polymorphism that has been associated with accelerated fibrin stabilization and reduced rate of fibrinolysis. The contribution of Val34Leu to long term risk of recurrent myocardial infarction (MI) in patients with coronary stenting has not been conclusively established. The objective of the study was to examine the effects of Val34Leu on fibrin generation, platelet aggregation, and long term clinical outcomes in patients with coronary artery disease treated with dual antiplatelet therapy. Patients with angiographically documented coronary artery disease who were treated with aspirin and clopidogrel were enrolled (n = 211). Light transmittance aggregometry and plasma fibrin clot formation using thrombelastography (TEG) were determined. Genotyping of Val34Leu was performed using Taqman assay. Clinical events during follow up were recorded. Homozygous carriers of 34Leu variant had significantly shorter fibrin clot formation time as compared to wild type individuals (TEG K: 1.27 ± 0.3 vs. 1.68 ± 1.1 min, p = 0.011). The Val34Leu variant was associated with gene dose dependent increased risk of MI (log rank, p = 0.002) or occurrence of composite of MI and CV death (log rank, p = 0.005) with highest event rates observed in homozygous carriers of 34Leu. In summary, FXIII Val34Leu polymorphism was associated with increased rate of fibrin stabilization in homozygous carriers of the variant and may increase risk of recurrent MI and death in patients with angiographically established coronary artery disease treated with dual antiplatelet therapy.     

Silencing of a metaphase I-specific gene results in a phenotype similar to that of the Pairing homeologous 1 (Ph1) gene mutations

Although studied extensively since 1958, the molecular mode of action of the Pairing homeologous 1 (Ph1) gene is still unknown. In polyploid wheat, the diploid-like chromosome pairing is principally controlled by the Ph1 gene via preventing homeologous chromosome pairing (HECP). Here, we report a candidate Ph1 gene (C-Ph1) present in the Ph1 locus, transient as well as stable silencing of which resulted in a phenotype characteristic of the Ph1 gene mutants, including HECP, multivalent formation, and disrupted chromosome alignment on the metaphase I (MI) plate. Despite a highly conserved DNA sequence, the C-Ph1 gene homeologues showed a dramatically different structure and expression pattern, with only the 5B copy showing MI-specific expression, further supporting our claim for the Ph1 gene. In agreement with the previous reports about the Ph1 gene, the predicted protein of the 5A copy of the C-Ph1 gene is truncated, and thus perhaps less effective. The 5D copy is expressed around the onset of meiosis; thus, it may function during the earlier stages of chromosome pairing. Along with alternate splicing, the predicted protein of the 5B copy is different from the protein of the other two copies because of an insertion. These structural and expression differences among the homeologues concurred with the previous observations about Ph1 gene function. Stable RNAi silencing of the wheat gene in Arabidopsis showed multivalents and centromere clustering during meiosis I.The Pairing homeologous 1 (Ph1) gene was discovered in 1958 based on the observation that plants lacking wheat chromosome 5B exhibit homeologous pairing (1, 2). Lack of the gene results in multivalents during metaphase I (MI) of meiosis, resulting in partial sterility. Conversely, six doses of the gene in the triisosomic line of chromosome 5BL resulted in interlocking of the bivalents and reduced chiasmata frequency even among homologs, along with rare multivalents (3). Several other genes promoting or suppressing homeologous chromosome pairing (HECP) have also been reported (4, 5), although their effect is difficult to measure in the presence of the Ph1 gene (6). Ph1-like genes were also reported in other sexually propagating polyploids, including Avena sativa, Festuca arundinacea, Brassica napus, Gossypium hirsutum, and Gossypium barbadense, as well as in some diploids, including Lolium perenne, Lolium multiflorum, and Lolium rigidum (7–11).Ph1 gene mutants in tetraploid (ph1c) (12, 13) and hexaploid (ph1b) (14) wheat were shown to be interstitial deletions involving an ∼0.84-μm region and an ∼1.05-μm region around the gene, respectively (15, 16) (SI Appendix, Fig. S1). Physical mapping localized the gene to an ∼2.5-Mb chromosomal region referred to as “Ph1 gene region,” bracketed by the distal breakpoint of ph1c deletion on the distal end and the breakpoint of deletion line 5BL-1 on the proximal end (16) (SI Appendix, Fig. S1). Various marker enrichment efforts identified nine markers for the region (17). Detailed microsynteny analyses and comparative mapping identified a 450-kb region of rice chromosome 9 (17). The corresponding rice region contained 91 genes. The major objective of the present study is to identify the gene(s) responsible for the Ph1 gene-like function using the available mapping information.     

High nodal FDG uptake increases risk of distant metastasis in patients with oropharyngeal squamous cell carcinoma

European Journal of Nuclear Medicine and Molecular Imaging - The purpose of this study was to investigate if FDG uptake metrics in primary tumor and lymph node metastases in patients with...     

Increasing use of anticoagulants in Germany and its impact on hospitalization rates for genitourinary bleeding

Journal of Thrombosis and Thrombolysis - The aim of the study was to compare nationwide time trends of prescribed oral anticoagulants (OAC) with the time trend of genitourinary bleedings (GUB) in...     

Reamed intramedullary exchange nailing: treatment of choice of aseptic femoral shaft nonunion

Background

There has been much controversy over specific tests for diagnosis of supraspinatus tendon tear. The aim of this study was to evaluate the metabolic activity of the deltoid and rotator cuff muscles while maintaining the full-can and empty-can testing positions using 2-deoxy-2-[¹⁸F]fluoro-D-glucose (¹⁸F-FDG) positron emission tomography (PET)/computed tomography (CT).

Methods

Ten healthy volunteers without shoulder pain or diabetes mellitus participated in this study. Following FDG injection, both arms were maintained in either the empty-can or full-can position for 10 min. PET/CT was performed 40 min after injection. Maximum standardized uptake values (SUVs) were measured in the deltoid and rotator cuff muscles on axial PET images.

Results

The middle deltoid exhibited the most significant increase in muscle activity at both testing positions. Additionally, a significant increase in muscle activity was observed in the middle deltoid compared with the supraspinatus (P < 0.05) in the empty-can testing position. SUVs of the middle deltoid, supraspinatus, and subscapularis showed a significant increase in the empty-can testing position compared with the full-can testing position (P < 0.05).

Conclusions

Significantly increased activity of the supraspinatus in conjunction with the middle deltoid and subscapularis after empty-can testing may result in decreased specificity of the empty-can test in detecting isolated supraspinatus activity. The full-can test, however, may be used to test the function of the supraspinatus with the least amount of surrounding middle deltoid and subscapularis activity.