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In the European Organisation for Research and Treatment of Cancer (EORTC)/GMDSSG phase III trial 06011, we compared decitabine (15 mg/m 2 every 8 h for 3 days) with best supportive care (BSC) in patients ≥60 years with myelodysplastic syndromes (MDS) by French-American-British (FAB) criteria. Here, we reinvestigate trial 06011 for the activity and efficacy specifically in patients with refractory anemia with excess blasts in transformation (RAEBt). Response rates in the decitabine arm ( N  = 40) were as follows: complete or partial remission, 15 %; hematologic improvement, 15 %; resistant disease, 30 %. RAEBt patients in the decitabine arm had longer progression-free survival (PFS; hazard ratio (HR) 0.30, 95 % confidence interval (CI) 0.18–0.51; median, 6.2 vs 2.8 months) and overall survival (OS; HR 0.68, 95 % CI 0.42–1.11; median, 8.0 vs 6.0 months) than in the BSC arm ( N  = 35). Censoring at allogeneic hematopoietic stem cell transplantation, the OS difference between the treatment groups increased, particularly among patients aged 60–74 years (HR 0.48, 95 % CI 0.26–0.89). After regrouping the study cohort according to World Health Organization (WHO) criteria, patients with acute myeloid leukemia (AML) (i.e., ≥20 % blasts) in the decitabine arm ( N  = 27) also had longer PFS than in the BSC arm ( N  = 23) (HR 0.46, 95 % CI 0.26–0.83; median, 6.2 vs 2.8 months). In conclusion, 3-day decitabine displays clinical activity and efficacy in MDS and/or AML with 5–30 % blood or 20–30 % marrow blasts.

Lung injury is frequently a component of the polytrauma sustained by military personnel surviving blast on the battlefield. This article describes a case series of the military casualties admitted to University Hospital Birmingham's critical care services (role 4 facility), during the period 1 July 2008 to 15 January 2010. Of the 135 casualties admitted, 107 (79.2%) were injured by explosive devices. Plain chest films taken soon after arrival in the role 4 facility were reviewed in 96 of the 107 patients. In 55 (57.3%) films a tracheal tube was present. One or more radiological abnormalities was present in 66 (68.75%) of the films. Five patients met the consensus criteria for the definition of adult respiratory distress syndrome (ARDS). The majority of casualties with blast-related lung injury were successfully managed with conventional ventilatory support employing a lung protective strategy; only a small minority received non-conventional support at any time in the form of high-frequency oscillatory ventilation. Of those casualties who survived to be received by the role 4 facility, none subsequently died as a consequence of lung injury.

Blast injuries have been increasing in the civilian setting and clinicians need to understand the spectrum of injury and management strategies. Multisystem trauma associated with combined blunt and penetrating injuries is the rule. Explosions in closed spaces increase the likelihood of primary blast injury. Rupture of tympanic membranes is an inaccurate marker for severe primary blast injury. Blast lung injury manifests early and should be managed with lung-protective ventilation. Blast brain injury is more common than previously appreciated.

Patients with chemo-refractory acute myeloid leukemia (AML) have a dismal prognosis. Chimeric antigen receptor T (CART) cell therapy has produced exciting results in CD19+ malignancies and may overcome many of the limitations of conventional leukemia therapies. We developed CART cells to target CD33 (CART33) using the anti-CD33 single chain variable fragment used in gemtuzumab ozogamicin (clone My96) and tested the activity and toxicity of these cells. CART33 exhibited significant effector functions in vitro and resulted in eradication of leukemia and prolonged survival in AML xenografts. CART33 also resulted in human lineage cytopenias and reduction of myeloid progenitors in xenograft models of hematopoietic toxicity, suggesting that permanently expressed CD33-specific CART cells would have unacceptable toxicity. To enhance the viability of CART33 as an option for AML, we designed a transiently expressed mRNA anti-CD33 CAR. Gene transfer was carried out by electroporation into T cells and resulted in high-level expression with potent but self-limited activity against AML. Thus our preclinical studies show potent activity of CART33 and indicate that transient expression of anti-CD33 CAR by RNA modification could be used in patients to avoid long-term myelosuppression. CART33 therapy could be used alone or as part of a preparative regimen prior to allogeneic transplantation in refractory AML.

Mild traumatic brain injury (mTBI) secondary to blast exposure is the most common battlefield injury in Southwest Asia. There has been little prospective work in the combat setting to test the efficacy of new countermeasures. The goal of this study was to compare the efficacy of N-acetyl cysteine (NAC) versus placebo on the symptoms associated with blast exposure mTBI in a combat setting. This study was a randomized double blind, placebo-controlled study that was conducted on active duty service members at a forward deployed field hospital in Iraq. All symptomatic U.S. service members who were exposed to significant ordnance blast and who met the criteria for mTBI were offered participation in the study and 81 individuals agreed to participate. Individuals underwent a baseline evaluation and then were randomly assigned to receive either N-acetyl cysteine (NAC) or placebo for seven days. Each subject was re-evaluated at 3 and 7 days. Outcome measures were the presence of the following sequelae of mTBI: dizziness, hearing loss, headache, memory loss, sleep disturbances, and neurocognitive dysfunction. The resolution of these symptoms seven days after the blast exposure was the main outcome measure in this study. Logistic regression on the outcome of 'no day 7 symptoms' indicated that NAC treatment was significantly better than placebo (OR = 3.6, p = 0.006). Secondary analysis revealed subjects receiving NAC within 24 hours of blast had an 86% chance of symptom resolution with no reported side effects versus 42% for those seen early who received placebo. This study, conducted in an active theatre of war, demonstrates that NAC, a safe pharmaceutical countermeasure, has beneficial effects on the severity and resolution of sequelae of blast induced mTBI. This is the first demonstration of an effective short term countermeasure for mTBI. Further work on long term outcomes and the potential use of NAC in civilian mTBI is warranted. ClinicalTrials.gov NCT00822263.

Blast traumatic brain injury (bTBI) is a prominent military health concern. The pervasiveness and long-term impacts of this injury highlight the need for investigation of the physiological outcomes of bTBI. Preclinical models allow for the evaluation of behavioral and neuropathological sequelae associated with bTBI. Studies have implemented rodent models to investigate bTBI due to the relative small size and low cost; however, a large animal model with similar neuroanatomical structure to humans is essential for clinical translation. Small blast simulators are used to induce bTBI in rodents, but a large animal model demands a larger device. This study describes a large advanced blast simulator (ABS4) that is a gas-detonation-driven system consisting of 5 sections totaling 40 ft in length with a cross-section of 4 × 4 ft at the test section. It is highly suitable for large animals and human surrogate investigations. This work characterized the ABS4 in preparation of large-scale bTBI testing. An array of tests were conducted with target overpressures in the test section ranging from 10 to 50 psi, and the pressure-time profiles clearly illustrate the essential characteristics of a free-field blast wave, specifically a sharp peak pressure and a defined negative phase. Multiple blast tests conducted at the same target pressure produced very similar pressure profiles, exhibiting the reproducibility of the ABS4 system. With its extensive range of pressures and substantial size, the ABS4 will permit military-relevant translational blast testing.

Military personnel involved in Operations Enduring Freedom and Iraqi Freedom (OEF/OIF) commonly experience blast-induced mild to moderate traumatic brain injury (TBI). In this study, we used task-activated functional MRI (fMRI) to determine if blast-related TBI has a differential impact on brain activation in comparison with TBI caused primarily by mechanical forces in civilian settings. Four groups participated: (1) blast-related military TBI (milTBI; n=21); (2) military controls (milCON; n=22); (3) non-blast civilian TBI (civTBI; n=21); and (4) civilian controls (civCON; n=23) with orthopedic injuries. Mild to moderate TBI (MTBI) occurred 1 to 6 years before enrollment. Participants completed the Stop Signal Task (SST), a measure of inhibitory control, while undergoing fMRI. Brain activation was evaluated with 2 (mil, civ)×2 (TBI, CON) analyses of variance, corrected for multiple comparisons. During correct inhibitions, fMRI activation was lower in the TBI than CON subjects in regions commonly associated with inhibitory control and the default mode network. In contrast, inhibitory failures showed significant interaction effects in the bilateral inferior temporal, left superior temporal, caudate, and cerebellar regions. Specifically, the milTBI group demonstrated more activation than the milCON group when failing to inhibit; in contrast, the civTBI group exhibited less activation than the civCON group. Covariance analyses controlling for the effects of education and self-reported psychological symptoms did not alter the brain activation findings. These results indicate that the chronic effects of TBI are associated with abnormal brain activation during successful response inhibition. During failed inhibition, the pattern of activation distinguished military from civilian TBI, suggesting that blast-related TBI has a unique effect on brain function that can be distinguished from TBI resulting from mechanical forces associated with sports or motor vehicle accidents. The implications of these findings for diagnosis and treatment of TBI are discussed.

The majority of patients injured in the recent conflicts in Iraq and Afghanistan were as a result of explosion, and terrorist incidents have brought blast injuries to the front door of many civilian hospitals that had not previously encountered such devastation. This article reviews the physics and pathophysiology of blast injury with particular relevance to the presentation and management of primary blast injury, which is the mechanism least familiar to most clinicians and which may cause devastating injury without externals signs.

A numerical simulation procedure is proposed for analyzing the partial replacement of pulverized coal injection by hydrogen, oxygen, and blast furnace gas (BFG) injections mixed with pulverized coal (PCI) within the tuyeres of large blast furnaces. The massive use of hydrogen-rich gas is extremely interesting for ironmaking blast furnaces in the context of net-zero carbon hot metal production. Likewise, this new approach allows for increasing productivity and for reducing the specific emissions of carbon dioxide toward a net-zero carbon ironmaking technology. Nevertheless, the mixture of pulverized coal injection and gas injection is a complex technology. In addition to the impact on chemical reactions and energy exchange, the internal temperature and gas flow patterns can also change drastically. With a view to assessing the state of the furnace in this complex operation, a comprehensive mathematical model utilizing multiphase theory was developed. The model simultaneously handles bulk solids (sinter, pellets, small coke, granular coke, and also iron ore), gas, liquid metal and slag, and coal powder phases. The associated conservation equations take into account momentum, mass, chemical species, and energy while being discretized and solved using finite volume techniques. The numerical model was validated against the reference operating conditions using 220 kg per ton of pig iron (kg/tHM) of pulverized coal. Therefore, the combined injection of different concentrations of fuel hydrogen, blast furnace gas, and oxygen was simulated for replacing 40, 60, and 80 kg/tHM of coal injection. Theoretical analysis showed that the best scenario with stable operation conditions could be achieved with a productivity increase of 20% corresponding to a CO2 reduction of 15% and 60 kg/tHM of PCI replacement.