Denosumab in men receiving androgen-deprivation therapy for prostate cancer.

Androgen-deprivation therapy is well-established for treating prostate cancer but is associated with bone loss and an increased risk of fracture. We investigated the effects of denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor-kappaB ligand, on bone mineral density and fractures in men receiving androgen-deprivation therapy for nonmetastatic prostate cancer. In this double-blind, multicenter study, we randomly assigned patients to receive denosumab at a dose of 60 mg subcutaneously every 6 months or placebo (734 patients in each group). The primary end point was percent change in bone mineral density at the lumbar spine at 24 months. Key secondary end points included percent change in bone mineral densities at the femoral neck and total hip at 24 months and at all three sites at 36 months, as well as incidence of new vertebral fractures. At 24 months, bone mineral density of the lumbar spine had increased by 5.6% in the denosumab group as compared with a loss of 1.0% in the placebo group (P<0.001); significant differences between the two groups were seen at as early as 1 month and sustained through 36 months. Denosumab therapy was also associated with significant increases in bone mineral density at the total hip, femoral neck, and distal third of the radius at all time points. Patients who received denosumab had a decreased incidence of new vertebral fractures at 36 months (1.5%, vs. 3.9% with placebo) (relative risk, 0.38; 95% confidence interval, 0.19 to 0.78; P=0.006). Rates of adverse events were similar between the two groups. Denosumab was associated with increased bone mineral density at all sites and a reduction in the incidence of new vertebral fractures among men receiving androgen-deprivation therapy for nonmetastatic prostate cancer. (ClinicalTrials.gov number, NCT00089674.

Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia.

In acute myeloid leukaemia (AML), the cell of origin, nature and biological consequences of initiating lesions, and order of subsequent mutations remain poorly understood, as AML is typically diagnosed without observation of a pre-leukaemic phase. Here, highly purified haematopoietic stem cells (HSCs), progenitor and mature cell fractions from the blood of AML patients were found to contain recurrent DNMT3A mutations (DNMT3A(mut)) at high allele frequency, but without coincident NPM1 mutations (NPM1c) present in AML blasts. DNMT3A(mut)-bearing HSCs showed a multilineage repopulation advantage over non-mutated HSCs in xenografts, establishing their identity as pre-leukaemic HSCs. Pre-leukaemic HSCs were found in remission samples, indicating that they survive chemotherapy. Therefore DNMT3A(mut) arises early in AML evolution, probably in HSCs, leading to a clonally expanded pool of pre-leukaemic HSCs from which AML evolves. Our findings provide a paradigm for the detection and treatment of pre-leukaemic clones before the acquisition of additional genetic lesions engenders greater therapeutic resistance

Tranexamic acid for acute gastrointestinal bleeding (the HALT-IT trial): statistical analysis plan for an international, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Acute gastrointestinal (GI) bleeding is an important cause of mortality worldwide. Bleeding can occur from the upper or lower GI tract, with upper GI bleeding accounting for most cases. The main causes include peptic ulcer/erosive mucosal disease, oesophageal varices and malignancy. The case fatality rate is around 10% for upper GI bleeding and 3% for lower GI bleeding. Rebleeding affects 5-40% of patients and is associated with a four-fold increased risk of death. Tranexamic acid (TXA) decreases bleeding and the need for blood transfusion in surgery and reduces death due to bleeding in patients with trauma and postpartum haemorrhage. It reduces bleeding by inhibiting the breakdown of fibrin clots by plasmin. Due to the methodological weaknesses and small size of the existing trials, the effectiveness and safety of TXA in GI bleeding is uncertain. The Haemorrhage ALleviation with Tranexamic acid - Intestinal system (HALT-IT) trial aims to provide reliable evidence about the effects of TXA in acute upper and lower GI bleeding. METHODS: The HALT-IT trial is an international, randomised, double-blind, placebo-controlled trial of tranexamic acid in 12,000 adults (increased from 8000) with acute upper or lower GI bleeding. Eligible patients are randomly allocated to receive TXA (1-g loading dose followed by 3-g maintenance dose over 24 h) or matching placebo. The main analysis will compare those randomised to TXA with those randomised to placebo on an intention-to-treat basis, presenting the results as effect estimates (relative risks) and confidence intervals. The primary outcome is death due to bleeding within 5 days of randomisation and secondary outcomes are: rebleeding; all-cause and cause-specific mortality; thromboembolic events; complications; endoscopic, radiological and surgical interventions; blood transfusion requirements; disability (defined by a measure of patient's self-care capacity); and number of days spent in intensive care or high-dependency units. Subgroup analyses for the primary outcome will consider time to treatment, location of bleeding, cause of bleed and clinical Rockall score. DISCUSSION: We present the statistical analysis of the HALT-IT trial. This plan was published before the treatment allocation was unblinded. TRIAL REGISTRATION: Current Controlled Trials, ID: ISRCTN11225767. Registered on 3 July 2012; Clinicaltrials.gov, ID: NCT01658124. Registered on 26 July 2012

Cold bonding of iron ore concentrate pellets

© 2015 Taylor & Francis Group, LLC. Iron ore concentrate pellets are traditionally hardened at high temperatures in horizontal grates and grate-kiln furnaces. However, heat induration requires tremendous quantities of energy to produce high-quality pellets, and is consequently expensive. Cold bonding is a low-temperature alternative to heat induration. Pellets can be cold bonded using lime, cement, sponge iron powder, and organic materials such as starch and flour. Cold bonding consumes less energy than heat induration, and has found favor for bonding self-reducing pellets and for refractory ores that are difficult to heat-treat. Herein, we review the principal cold bonding methods and their fundamentals

Iron ore pellet dustiness part I: Factors affecting dust generation

© 2015 Taylor and Francis Group, LLC. Iron ore pellets abrade during handling and produce dust. This study was conducted to determine what factors affect pellet dustiness, and whether dustiness can be related to the abrasion index. Factors studied included bed depth within a straight grate furnace; pellet chemistry; firing temperature; coke breeze addition; and tumble index. Abrasion indices for all pellet samples ranged from 1.9-5.0% (20 samples) and from 7.1-27.5% (5 samples). Pellets were dropped in an enclosed tower, which enabled the collection of airborne particles generated during pellet breakdown. The quantity of airborne particles generated by each pellet type was 10-100 mg/kg-drop, or 50-500 mg/kg over five drops through the tower. Pellet dustiness was predominantly affected by pellet chemistry and by pellet firing temperature. Results showed a nearly 21% increase in dustiness for every percent decrease in firing temperature-this was based on a typical firing temperature of 1280°C. Pellet dustiness was regressed to the pellet abrasion index (for AI \u3c 5%), which yielded a correlation coefficient of 0.22. These results show that, although AI is one of the best indicators of fired pellet quality and can indicate high levels of dust, it could not explain the dustiness of good quality pellets.The second paper (Iron Ore Pellet Dustiness Part II) explains the relationship between AI and dust for good-quality pellets; and compares fines generation between pellets fired in Straight-Grate (Traveling Grate) and Grate-Kiln furnaces