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1
Saiki, H., G. Ngaile, and L. Ruan. "Characterization of Adhesive Strength of Phosphate Coatings in Cold Metal Forming." Journal of Tribology 119, no. 4 (October 1, 1997): 667–71. http://dx.doi.org/10.1115/1.2833867.
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A test method is proposed to characterize adhesive strength of phosphate coatings based on the various deformation patterns at the tool-workpiece interface. The deformation patterns were induced by tools of different surface geometrical profiles, i.e., flat surface, sinusoidal surface, saw-tooth surface and multi-surface profiles, in a localized rod drawing technique. With change in the tool geometry, three deformation regimes were observed, i.e., full film lubrication regime, mixed regime, and seizure regimes, which were categorized by the level of friction coefficient attained, and the degree of galling observed on the surface of the drawn specimens. The full film lubrication regimes were noticed when flat dies were used. In this case, the friction coefficient was maintained at nearly μ = 0.065, irrespective of the change in the surface roughness of the tools and reduction. With sinusoidal surface and other non-flat dies, mixed regime and seizure regimes were observed, and the friction coefficient varied from μ = 0.1 to 0.3. To complement the friction data, surface analysis of the tool-workpiece interface was also conducted. The frictional range of μ = 0.065 to 0.3 obtained in this study, therefore, provides for a manageable characterization of phosphate coatings for cold metal forming of objects with intricate shapes.
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Ionita, Valentin, Lucian Petrescu, and Emil Cazacu. "Improved estimation of iron losses for non-sinusoidal voltages." COMPEL - The international journal for computation and mathematics in electrical and electronic engineering 37, no. 5 (September 3, 2018): 1698–706. http://dx.doi.org/10.1108/compel-12-2017-0527.
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Purpose The electrical machines connected to modern electric power grids are non-sinusoidal excited, and their augmented losses, including iron losses, limit their working characteristics. This paper aims to propose a prediction method for iron losses in non-oriented grains (NO) FeSi sheets under non-sinusoidal voltage, involving an inverse classical Preisach hysteresis model and the time-integration of each loss component. Design/methodology/approach The magnetic history management in inverse Preisach model is optimized and a numerical Everett function is identified from measured symmetrical hysteresis cycles. The experimental data for sinusoidal waveforms obtained by a single sheet tester were also used to identify the parameters involved in Bertotti’ losses separation method. The non-sinusoidal magnetic induction waveform, corresponding to a measured voltage in an industrial electrical grid, was the input for Preisach model, the output magnetic field being accurately computed. The hysteresis, classical and excess losses are calculated by time-integration and the total losses are compared with those obtained for sinusoidal excitation. Findings The proposed method allows to estimate the iron losses for non-sinusoidal magnetic induction, using carefully identified parameters of FeSi NO sheets, using experimental data from sinusoidal regimes. Originality/value The method accuracy is assured by using a numerical Everett function, a variable Preisach grid step (adapted for the high non-linearity of FeSi sheets) and high-order fitting polynomials for the microscopic parameters involved in the excess loss estimation. The procedure allows a better design of magnetic cores and an improved estimation of the electric machine derating for non-sinusoidal voltages.
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Krishnakumaran, R., Mohammed Raees, and Supratim Ray. "Shape analysis of gamma rhythm supports a superlinear inhibitory regime in an inhibition-stabilized network." PLOS Computational Biology 18, no. 2 (February 14, 2022): e1009886. http://dx.doi.org/10.1371/journal.pcbi.1009886.
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Visual inspection of stimulus-induced gamma oscillations (30–70 Hz) often reveals a non-sinusoidal shape. Such distortions are a hallmark of non-linear systems and are also observed in mean-field models of gamma oscillations. A thorough characterization of the shape of the gamma cycle can therefore provide additional constraints on the operating regime of such models. However, the gamma waveform has not been quantitatively characterized, partially because the first harmonic of gamma, which arises because of the non-sinusoidal nature of the signal, is typically weak and gets masked due to a broadband increase in power related to spiking. To address this, we recorded local field potential (LFP) from the primary visual cortex (V1) of two awake female macaques while presenting full-field gratings or iso-luminant chromatic hues that produced huge gamma oscillations with prominent peaks at harmonic frequencies in the power spectra. We found that gamma and its first harmonic always maintained a specific phase relationship, resulting in a distinctive shape with a sharp trough and a shallow peak. Interestingly, a Wilson-Cowan (WC) model operating in an inhibition stabilized mode could replicate this shape, but only when the inhibitory population operated in the super-linear regime, as predicted recently. However, another recently developed model of gamma that operates in a linear regime driven by stochastic noise failed to produce salient harmonics or the observed shape. Our results impose additional constraints on models that generate gamma oscillations and their operating regimes.
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Gsell, Simon, Rémi Bourguet, and Marianna Braza. "Vortex-induced vibrations of a cylinder in planar shear flow." Journal of Fluid Mechanics 825 (July 20, 2017): 353–84. http://dx.doi.org/10.1017/jfm.2017.386.
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The system composed of a circular cylinder, either fixed or elastically mounted, and immersed in a current linearly sheared in the cross-flow direction, is investigated via numerical simulations. The impact of the shear and associated symmetry breaking are explored over wide ranges of values of the shear parameter (non-dimensional inflow velocity gradient, $\unicode[STIX]{x1D6FD}\in [0,0.4]$) and reduced velocity (inverse of the non-dimensional natural frequency of the oscillator, $U^{\ast }\in [2,14]$), at Reynolds number $Re=100$; $\unicode[STIX]{x1D6FD}$, $U^{\ast }$ and $Re$ are based on the inflow velocity at the centre of the body and on its diameter. In the absence of large-amplitude vibrations and in the fixed body case, three successive regimes are identified. Two unsteady flow regimes develop for $\unicode[STIX]{x1D6FD}\in [0,0.2]$ (regime L) and $\unicode[STIX]{x1D6FD}\in [0.2,0.3]$ (regime H). They differ by the relative influence of the shear, which is found to be limited in regime L. In contrast, the shear leads to a major reconfiguration of the wake (e.g. asymmetric pattern, lower vortex shedding frequency, synchronized oscillation of the saddle point) and a substantial alteration of the fluid forcing in regime H. A steady flow regime (S), characterized by a triangular wake pattern, is uncovered for $\unicode[STIX]{x1D6FD}>0.3$. Free vibrations of large amplitudes arise in a region of the parameter space that encompasses the entire range of $\unicode[STIX]{x1D6FD}$ and a range of $U^{\ast }$ that widens as $\unicode[STIX]{x1D6FD}$ increases; therefore vibrations appear beyond the limit of steady flow in the fixed body case ($\unicode[STIX]{x1D6FD}=0.3$). Three distinct regimes of the flow–structure system are encountered in this region. In all regimes, body motion and flow unsteadiness are synchronized (lock-in condition). For $\unicode[STIX]{x1D6FD}\in [0,0.2]$, in regime VL, the system behaviour remains close to that observed in uniform current. The main impact of the shear concerns the amplification of the in-line response and the transition from figure-eight to ellipsoidal orbits. For $\unicode[STIX]{x1D6FD}\in [0.2,0.4]$, the system exhibits two well-defined regimes: VH1 and VH2 in the lower and higher ranges of $U^{\ast }$, respectively. Even if the wake patterns, close to the asymmetric pattern observed in regime H, are comparable in both regimes, the properties of the vibrations and fluid forces clearly depart. The responses differ by their spectral contents, i.e. sinusoidal versus multi-harmonic, and their amplitudes are much larger in regime VH1, where the in-line responses reach $2$ diameters ($0.03$ diameters in uniform flow) and the cross-flow responses $1.3$ diameters. Aperiodic, intermittent oscillations are found to occur in the transition region between regimes VH1 and VH2; it appears that wake–body synchronization persists in this case.
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Hu, Qiang-Qiang, and Yong-Liang Yu. "The hydrodynamic effects of undulating patterns on propulsion and braking performances of long-based fin." AIP Advances 12, no. 3 (March 1, 2022): 035319. http://dx.doi.org/10.1063/5.0083912.
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Bio-inspired long-based undulating fin propulsion is commonly employed in biological autonomous underwater vehicles (BAUVs), while the hydrodynamic characteristics of various undulating patterns are different. To investigate what kind of undulating pattern has outstanding propulsion or braking performance for BAUVs in directional maneuvers, undulations with four basic undulating patterns are numerically examined under the Open-source Field Operation And Manipulation environment at the Reynolds number of 5 × 102, 5 × 103, and 5 × 104, corresponding to viscous, transitional, and inertial flow regimes, respectively. The study is conducted at various non-dimensional phase speeds c (0.5–2.0, normalized by incoming flow speed) at a constant maximum amplitude of 0.08 and a wavelength of 0.5 (both are normalized by the fin cord length) to imitate the long-based fin. The numerical results indicate that the undulating fin motion with the amplitude envelope gradually increasing from the anterior part to the posterior (conical sinusoidal wave) part may be preferable for thrust generation; undulating with the amplitude envelope increasing from the anterior part to the mid part and decreasing toward the posterior (fusiform sinusoidal wave) presents the superior braking performance when the phase speed is low enough. Moreover, the influence of undulating patterns on the wake structure is analyzed. Through further comparative analysis for propulsion and braking performances, the results obtained here may have instructional significance to the propulsion mechanism in bionic design.
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Tutty, O. R., and T. J. Pedley. "Oscillatory flow in a stepped channel." Journal of Fluid Mechanics 247 (February 1993): 179–204. http://dx.doi.org/10.1017/s0022112093000436.
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Two-dimensional, unsteady flow of a viscous, incompressible fluid in a stepped channel has been studied by the numerical solution of the Navier–Stokes equation using an accurate finite-difference method.With a sinusoidal mass flow rate, the problem has three governing parameters: the Reynolds number, the Strouhal number, and the step height. The effects on the flow of varying all three parameters has been investigated systematically. In appropriate parameter regimes, a strong ‘vortex wave’ is generated during the forward phase when the flow is over the step into the expansion. Secondary effects on the wave can result in a complex flow pattern with each major structure of the flow consisting of an eddy with more than one core. No such wave is found during the reverse phase of the flow. The generation and development of the wave is examined in some detail, and our results are compared and contrasted with those of previous studies, both experimental and theoretical, of flow in non-uniform vessels.
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Cheng, W., D. I. Pullin, and R. Samtaney. "Large-eddy simulation of flow over a grooved cylinder up to transcritical Reynolds numbers." Journal of Fluid Mechanics 835 (November 27, 2017): 327–62. http://dx.doi.org/10.1017/jfm.2017.767.
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We report wall-resolved large-eddy simulation (LES) of flow over a grooved cylinder up to the transcritical regime. The stretched-vortex subgrid-scale model is embedded in a general fourth-order finite-difference code discretization on a curvilinear mesh. In the present study $32$ grooves are equally distributed around the circumference of the cylinder, each of sinusoidal shape with height $\unicode[STIX]{x1D716}$, invariant in the spanwise direction. Based on the two parameters, $\unicode[STIX]{x1D716}/D$ and the Reynolds number $Re_{D}=U_{\infty }D/\unicode[STIX]{x1D708}$ where $U_{\infty }$ is the free-stream velocity, $D$ the diameter of the cylinder and $\unicode[STIX]{x1D708}$ the kinematic viscosity, two main sets of simulations are described. The first set varies $\unicode[STIX]{x1D716}/D$ from $0$ to $1/32$ while fixing $Re_{D}=3.9\times 10^{3}$. We study the flow deviation from the smooth-cylinder case, with emphasis on several important statistics such as the length of the mean-flow recirculation bubble $L_{B}$, the pressure coefficient $C_{p}$, the skin-friction coefficient $C_{f\unicode[STIX]{x1D703}}$ and the non-dimensional pressure gradient parameter $\unicode[STIX]{x1D6FD}$. It is found that, with increasing $\unicode[STIX]{x1D716}/D$ at fixed $Re_{D}$, some properties of the mean flow behave somewhat similarly to changes in the smooth-cylinder flow when $Re_{D}$ is increased. This includes shrinking $L_{B}$ and nearly constant minimum pressure coefficient. In contrast, while the non-dimensional pressure gradient parameter $\unicode[STIX]{x1D6FD}$ remains nearly constant for the front part of the smooth cylinder flow, $\unicode[STIX]{x1D6FD}$ shows an oscillatory variation for the grooved-cylinder case. The second main set of LES varies $Re_{D}$ from $3.9\times 10^{3}$ to $6\times 10^{4}$ with fixed $\unicode[STIX]{x1D716}/D=1/32$. It is found that this $Re_{D}$ range spans the subcritical and supercritical regimes and reaches the beginning of the transcritical flow regime. Mean-flow properties are diagnosed and compared with available experimental data including $C_{p}$ and the drag coefficient $C_{D}$. The timewise variation of the lift and drag coefficients are also studied to elucidate the transition among three regimes. Instantaneous images of the surface, skin-friction vector field and also of the three-dimensional Q-criterion field are utilized to further understand the dynamics of the near-surface flow structures and vortex shedding. Comparison of the grooved-cylinder flow with the equivalent flow over a smooth-wall cylinder shows structural similarities but significant differences. Both flows exhibit a clear common signature, which is the formation of mean-flow secondary separation bubbles that transform to other local flow features upstream of the main separation region (prior separation bubbles) as $Re_{D}$ is increased through the respective drag crises. Based on these similarities it is hypothesized that the drag crises known to occur for flow past a cylinder with different surface topographies is the result of a change in the global flow state generated by an interaction of primary flow separation with secondary flow recirculating motions that manifest as a mean-flow secondary bubble. For the smooth-wall flow this is accompanied by local boundary-layer flow transition to turbulence and a strong drag crisis, while for the grooved-cylinder case the flow remains laminar but unsteady through its drag crisis and into the early transcritical flow range.
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Ahmed, Gulraiz, Mathieu Sellier, Yeaw Chu Lee, Mark Jermy, and Michael Taylor. "Rheological effects on the levelling dynamics of thin fluid films." International Journal of Numerical Methods for Heat & Fluid Flow 25, no. 8 (November 2, 2015): 1850–67. http://dx.doi.org/10.1108/hff-10-2013-0295.
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Purpose – The purpose of this paper is to investigate numerically the effect of rheology on the leveling of thin fluid films on horizontal solid substrates. Design/methodology/approach – A mathematical model based on the lubrication approximation which defines non-Newtonian rheology using a Power-law model is presented. The rheology is described by two parameters: the consistency factor and the flow behavior index. The resulting highly non-linear coupled set of equations is discretized using Finite-Difference and the resulting algebraic system is solved via an efficient Multigrid algorithm. Findings – Importantly, the non-dimensionalization process leads to a pair of Partial Differential Equations which depends on one parameter only, the flow behavior index. The authors show that the consistency factor only affects the time scale of the leveling process, hence stretching or contracting the time line. Results for the leveling of sinusoidal perturbations of the fluid film highlights important differences between the leveling of shear-thinning and shear-thickening fluids. In a normalized time frame, the onset of leveling occurs earlier for the shear-thinning fluid than for the shear-thickening one. However, the dimensionless leveling rate is higher for the shear-thickening fluid than the shear-thinning one. This results in a “threshold thickness” which delimits two regimes: the shear-thinning fluid levels to a thickness above this threshold faster than the shear-thickening fluid but the opposite is true for a film thickness below this threshold. An important aspect of this study is the verification of the numerical implementation using the Method of Manufactured Solutions (MMS), a first in the context of thin film studies. The paper also highlights differences between the leveling of two-dimensional and three-dimensional thickness perturbations. Originality/value – The study of the leveling of disturbances at the free surface of a liquid film using a Power-law rheological model does not appear to have been covered in the literature. Also, the paper uses the MMS to test the validity of the implementation. This appears to be the first time it has been used in the context of the lubrication approximation. Finally, unlike most prior studies, the work does away with the planar assumption.
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DAREKAR, RUPAD M., and SPENCER J. SHERWIN. "Flow past a square-section cylinder with a wavy stagnation face." Journal of Fluid Mechanics 426 (January 10, 2001): 263–95. http://dx.doi.org/10.1017/s0022112000002299.
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Numerical investigations have been performed for the flow past square-section cylinders with a spanwise geometric deformation leading to a stagnation face with a sinusoidal waviness. The computations were performed using a spectral/hp element solver over a range of Reynolds numbers from 10 to 150.Starting from fully developed shedding past a straight cylinder at a Reynolds number of 100, a sufficiently high waviness is impulsively introduced resulting in the stabilization of the near wake to a time-independent state. It is shown that the spanwise waviness sets up a cross-flow within the growing boundary layer on the leading-edge surface thereby generating streamwise and vertical components of vorticity. These additional components of vorticity appear in regions close to the inflection points of the wavy stagnation face where the spanwise vorticity is weakened. This redistribution of vorticity leads to the breakdown of the unsteady and staggered Kármán vortex wake into a steady and symmetric near-wake structure. The steady nature of the near wake is associated with a reduction in total drag of about 16% at a Reynolds number of 100 compared with the straight, non-wavy cylinder.Further increases in the amplitude of the waviness lead to the emergence of hairpin vortices from the near-wake region. This wake topology has similarities to the wake of a sphere at low Reynolds numbers. The physical structure of the wake due to the variation of the amplitude of the waviness is identified with five distinct regimes. Furthermore, the introduction of a waviness at a wavelength close to the mode A wavelength and the primary wavelength of the straight square-section cylinder leads to the suppression of the Kármán street at a minimal waviness amplitude.
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Rob, R., C. Panoiu, and M. Panoiu. "Study regarding the non-sinusoidal regime imposed by nonlinear loads." IOP Conference Series: Materials Science and Engineering 106 (February 1, 2016): 012023. http://dx.doi.org/10.1088/1757-899x/106/1/012023.
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Ben Barouch, Sharon, Omri Cohen, Liat Vidal, Irit Avivi, and Ron Ram. "Busulfan Fludarabine Vs. Busulfan Cyclophosphamide As a Preparative Regimen Prior to Allogeneic Hematopoietic Cell Transplantation – Systematic Review and Meta-analysis." Blood 124, no. 21 (December 6, 2014): 3872. http://dx.doi.org/10.1182/blood.v124.21.3872.3872.
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Abstract Background: Both busulfan-cyclophosphamide (BuCy) and the reduced toxicity regimen busulfan-fludarabine (BuFlu) are considered myeloablative preparative regimens given prior to allogeneic hematopoietic cell transplantation (HCT). A comprehensive literature evaluation of BuFlu vs. BuCy is lacking and the question of the preferable regimen is still debatable. Objectives: We aimed to compare the efficacy and safety of BuFlu (intervention arm) vs. BuCy (comparable arm) as preparative regimens in patients given allografts. Methods: Systematic review and meta-analysis of all randomized controlled trials (RCTs) and non-randomized comparative trials of patients given BuFlu vs. BuCy as preparative regimens prior to allografts. Electronic search in the Cochrane Library, MEDLINE and conference proceedings was conducted up-to July 2014. Primary outcomes were all-cause mortality at 100 days and at the end of study. Secondary outcomes were time to neutrophil engraftment, primary & secondary rejection, risk for grade 3-4 mucositis, sinusoidal obstruction syndrome (SOS), microbiology documented infection, overall and grade 3-4 acute graft vs. host disease (GVHD), overall and extensive chronic GVHD, non-relapse mortality at 100 day and at the end of study, and relapse risk. For dichotomous data, relative risks (RR) with 95% confidence intervals (CIs) were estimated and pooled. For continuous variables we calculated weighted mean difference (WMD). Results: Our search yielded 14 trials recruiting 1578 patients. Three trials were RCTs and 11 were either one arm intervention trials compared to historical controls or retrospective studies. There were no differences in all-cause mortality at 100 days and end of study ( RR 0.85; 95% CI 0.56-1.30, 9 trials and RR 0.77; 95% CI 0.59-1.02, 12 trials, respectively), Figure, with similar results in sensitivity analyses including only RCTs and only studies in which patients' age and status of disease at HCT were well matched. Both primary and secondary rejections were comparable between the two regimens. Time to neutrophil engraftment was 1-day longer in patients given the BuCy regimen (WMD 0.84; 95% CI 0.37-1.31, 6 trials). Both the risks for SOS and microbiology documented infections were lower in the BuFlu patients (RR 0.34; 95% CI 0.19-0.62, 8 trials and RR 0.79; 95% CI 0.64-0.97, 2 trials, respectively). Grade 3-4 mucositis was comparable between the two groups. There was a lower incidence of grade 2-4 acute GVHD in patients given FluBu (RR 0.67; 95% CI 0.46-0.99, 10 trials), however this was no longer true in sensitivity analysis including only RCTs. There were no differences between the two arms in grade 3-4 acute GVHD, overall and extensive chronic GVHD, non-relapse mortality at 100 days and at the end of study and relapse risk. Conclusions: While toxicity profile of BuFlu regimen is safer than the classic BuCy regimen, this does not translate into composite transplantation outcomes. Patients at higher risk for SOS may benefit from the BuFlu regimen; however additional RCTs are required to identify other subgroups of patients who will benefit from a tailored-preparative regimen approach. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Eguiluz, L. I., and J. Arrillaga. "Comparison of Power Definitions in the Presence of Waveform Distortion." International Journal of Electrical Engineering & Education 32, no. 2 (April 1995): 141–53. http://dx.doi.org/10.1177/002072099503200205.
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Comparison of power definitions in the presence of waveform distortion In this paper, several definitions of reactive and apparent power in the non-sinusoidal regime are analysed and their repercussions in energy-billing are assessed. The classical method of optimisation by capacitor bank is considered to be problematic since it produces frequent resonances and increased harmonic distortion.
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Li, Xiao-Miao, Zhongbo Hu, Marda L. Jorgenson, John R. Wingard, and William B. Slayton. "Bone Marrow Sinusoidal Endothelium Undergoes DNA Damage and Repair Following Lethal Irradiation." Blood 110, no. 11 (November 16, 2007): 4866. http://dx.doi.org/10.1182/blood.v110.11.4866.4866.
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Abstract In the light of the possibility that adult bone marrow cells possess hemangioblast ability, work from our laboratory demonstrates that the bone marrow sinusoids remain predominantly host-derived following bone marrow transplant when ionizing irradiation is used as the conditioning regimen. To determine the effect of lethal irradiation to the host sinusoidal endothelial cells, we performed four apoptosis related assays and two cell proliferation assays on bone marrow sections at various time points during the first two weeks post-irradiation. We found: Phosphorylated H2AX was present in both hematopoietic and sinusoidal endothelial cells. However, only hematopoietic cells showed caspase-3 dependent apoptosis. Three days after radiation, some sinusoidal endothelial cells became TUNEL (Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay) positive, but were activated caspase-3 and ISOL (in situ oligo ligation assay) negative, suggesting non-apoptotic DNA fragmentation. TUNEL positive endothelial cells were present in non-transplanted irradiated bone marrow 7–13 days post-irradiation while after 7 days, there were almost no TUNEL positive endothelial cells in transplanted animal, demonstrating that donor cells support sinusoidal endothelial survival. In some endothelial cells, TUNEL signal was concentrated in discrete areas of the nucleus, suggesting a repair process that involves the localization and removal of damaged DNA fragments. Very few sinusoidal endothelial cells were Ki67 positive and even fewer were BrdU positive, demonstrating that endothelial cell division is not a major mechanism for the survival of bone marrow sinusoidal system after irradiation on the short term. These results demonstrate that sinusoidal endothelial cells undergo DNA damage and repair after lethal irradiation for bone marrow transplant. These results may explain, in part, why patients with impaired DNA damage/repair mechanisms have engraftment defects.
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NIKNAM, A. R., and B. SHOKRI. "Nonlinear dynamics of the filamentation of the resistive instability of a current-carrying plasma." Journal of Plasma Physics 74, no. 3 (June 2008): 319–26. http://dx.doi.org/10.1017/s0022377807006721.
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AbstractThe filamentation of the resistive instability in a weakly ionized quasi-neutral current-carrying plasma in the diffusion frequency region in the nonlinear regime is investigated. By using the magnetohydrodynamics equations and Ampere's law and assuming that the plasma is non-isothermal and inhomogeneous, the evolution of the magnetic field diffusion into the plasma is described by the Lienard nonlinear differential equation. Furthermore, it is shown that the departure of the profiles of the magnetic field and electron density variation from a sinusoidal shape in the nonlinear regime and a transverse filamentation and density steepening can occur in the static limit. Also, it is shown that the shape of the transverse filamentation can vary in this regime depending on the gradient of the magnetic field.
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Harris, Andrew C., Jaap Jan Boelens, Kwang Woo Ahn, Mingwei Fei, Allistair Abraham, Andrew Artz, Christopher C. Dvorak, et al. "Comparison of Outcomes for Myeloablative Conditioning Regimens Combining Busulfan with Either Cyclophosphamide or Fludarabine in Children." Blood 128, no. 22 (December 2, 2016): 664. http://dx.doi.org/10.1182/blood.v128.22.664.664.
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Abstract Myeloablative busulfan with cyclophosphamide (BuCy) has been the standard conditioning regimen for children with myeloid malignancies and certain non-malignant conditions. While effective, this regimen has historically high rates of regimen-related toxicities such as sinusoidal obstruction syndrome (SOS; 20-50%) and hemorrhagic cystitis (5%-15%). Substituting fludarabine for cyclophosphamide (BuFlu) has led to less toxicity and better outcomes in adult patients, prompting many pediatric centers to adopt this regimen despite sparse pediatric medical literature. We utilized the CIBMTR database to compare toxicity and outcomes of BuCy and BuFlu in pediatric patients. Methods: We identified 1781 patients aged 0-18 receiving a first allogeneic transplant with myeloablative BuCy (N=1400) or BuFlu (N=381) from 2008-2014. We excluded recipients of cord blood, T-cell depleted grafts and haplo-identical donors. The completeness index of follow up was 93% at 2 years. Transplant-related mortality (TRM), relapse and disease free survival (DFS) for patients with malignant diseases, and overall survival (OS) for all patients were compared between regimens. For a subset of patients with available comprehensive reporting (N=528; BuCy N=364, BuFlu N=164), we compared neutrophil and platelet engraftment, SOS, non-infectious hemorrhagic cystitis and pulmonary toxicity, graft failure, infections, acute and chronic GVHD between regimens. Results: For patients with non-malignant diseases (BuCy N=627, BuFlu N=176; Table 1), the BuFlu group had a higher proportion of patients with HCT-comorbidity index (HCT-CI) ≥3 and unrelated donors with single HLA-antigen mismatches. With BuCy, SOS and hemorrhagic cystitis occurred at historical rates and more frequently than BuFlu (16% vs. 7%, p=0.04, and 9% vs. 2%, p=0.04). BuFlu recipients experienced better platelet engraftment by day 28 (40% vs. 59%, p=0.005). There was no difference in graft failure, neutrophil engraftment, infections or GVHD (all p>0.05). There was no difference in 2-yr OS (p=0.8). On multivariate analysis, conditioning regimen had no impact on survival (p=0.5). For patients with malignant diseases (BuCy N=773; BuFlu N=205; Table 1), the BuFlu group had a higher proportion of patients with HCT CI ≥ 3, unrelated donors with single HLA-antigen mismatches, more frequent use of peripheral blood stem cells (PBSC) and ATG. BuFlu was associated with better day 28 neutrophil (91% vs 94%, p=0.002) and platelet engraftment (43% vs 67%, p<0.001), but no differences in engraftment at day 100. There were no differences in SOS (15% vs 13%, p=0.66), hemorrhagic cystitis, (8% vs 7%, p=0.75) pulmonary toxicity, infections and GVHD between regimens. Univariate analysis demonstrated inferior 2-year DFS (62% vs. 56%, p=0.03) and OS (71% vs. 61%, p=0.001) with BuFlu, but no significant differences in TRM or relapse. Multivariate analysis including only risk factors that were significant on multivariate analysis demonstrated higher mortality attributable to BuFlu (HR 1.4, p<0.008; Table 2), but not DFS. The most common indication for busulfan-based conditioning in children is acute myeloid leukemia (AML) in complete remission (CR). When analyzing the subset of patients with AML in CR (BuCy N=462, BuFlu N=118), there was no difference in SOS, hemorrhagic cystitis, pulmonary toxicity, acute or chronic GVHD, TRM, relapse, DFS or OS. Conclusions: The use of BuFlu in lieu of BuCy leads to faster engraftment and appeared to reduce the incidence of SOS and non-infectious hemorrhagic cystitis in patients with non-malignant diseases. Other outcomes appear comparable between regimens for patients transplanted for non-malignant diseases. Patients receiving BuFlu for malignancy experienced worse overall survival. These differences in survival were not evident for patients with AML in CR, although numbers were lower. BuFlu recipients were in general more infirm, received alternative donor grafts, PBSC or ATG more often, reflecting that the selection of conditioning was linked to specific transplant scenarios. Despite adjusting for known factors, isolating the sole impact of conditioning on survival is difficult. These findings require confirmation on prospective, randomized trials. Disclosures Nishihori: Novartis: Research Funding; Signal Genetics: Research Funding.
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Scorza, Daniela, Andrea Carpinteri, Giovanni Fortese, Camilla Ronchei, Sabrina Vantadori, and Andrea Zanichelli. "Multiaxial fatigue life estimation in low-cycle fatigue regime including the mean stress effect." MATEC Web of Conferences 165 (2018): 16002. http://dx.doi.org/10.1051/matecconf/201816516002.
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The goal of the present paper is to discuss the reliability of a strain-based multiaxial Low-Cycle Fatigue (LCF) criterion in estimating the fatigue lifetime of metallic structural components subjected to multiaxial sinusoidal loading with zero and non-zero mean value. Since it is well-known that a tensile mean normal stress reduces the fatigue life of structural components, three different models available in the literature are implemented in the present criterion in order to take into account the above mean stress effect. In particular, such a criterion is formulated in terms of strains by employing the displacement components acting on the critical plane and, then, by defining an equivalent strain related to such a plane. The Morrow model, the Smith-Watson-Topper model and the Manson-Halford model are applied to define such an equivalent strain. The effectiveness of the new formulations is evaluated through comparison with some experimental data reported in the literature, related to biaxial fatigue tests performed on metallic specimens under in-and out-of-phase loadings characterised by non-zero mean stress values.
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Dubrovina, Elizaveta, Richard V. Craster, and Demetrios T. Papageorgiou. "Two-layer electrified pressure-driven flow in topographically structured channels." Journal of Fluid Mechanics 814 (February 2, 2017): 222–48. http://dx.doi.org/10.1017/jfm.2017.17.
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The flow of two stratified viscous immiscible perfect dielectric fluids in a channel with topographically structured walls is investigated. The flow is driven by a streamwise pressure gradient and an electric field across the channel gap. This problem is explored in detail by deriving and studying a nonlinear evolution equation for the interface valid for large-amplitude long waves in the Stokes flow regime. For flat walls, the electrified flow is long-wave unstable with a critical cutoff wavenumber that increases linearly with the magnitude of the applied voltage. In the nonlinear regime, it is found that the presence of pressure-driven flow prevents electrostatically induced interface touchdown that has been observed previously – time-modulated nonlinear travelling waves emerge instead. When topography is present, linearly stable uniform flows become non-uniform spatially periodic steady states; a small-amplitude asymptotic theory is carried out and compared with computations. In the linearly unstable regime, intricate nonlinear structures emerge that depend, among other things, on the magnitude of the wall corrugations. For a low-amplitude sinusoidal boundary, time-modulated travelling waves are observed that are similar to those found for flat walls but are influenced by the geometry of the wall and slide over it without touching. The flow over a high-amplitude sinusoidal pattern is also examined in detail and it is found that for sufficiently large voltages the interface evolves to large-amplitude waves that span the channel and are subharmonic relative to the wall. A type of ‘walking’ motion emerges that causes the lower fluid to wash through the troughs and create strong vortices over the peaks of the lower boundary. Non-uniform steady states induced by the topography are calculated numerically for moderate and large values of the flow rate, and their stability is analysed using Floquet theory. The effect of large flow rates is also considered asymptotically to find solutions that compare very well with numerical computations.
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NIKITIN, A., N. G. STOCKS, and A. R. BULSARA. "NONLINEAR SIGNAL DETECTION IN THE TIME DOMAIN: LEVEL CROSSING STATISTICS AND NOISE-MEDIATED MINIMIZATION OF THE MEASUREMENT ERROR." Fluctuation and Noise Letters 04, no. 01 (March 2004): L63—L73. http://dx.doi.org/10.1142/s0219477504001665.
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We study the problem of detecting a small dc signal by quantifying its effect on the mean difference ΔT in residence times in the stable steady states of a bistable dynamical measurement device, in the presence of a noise-floor and a known time-sinusoidal bias signal. Errors in the measurement process occur due to a finite observation time that is present in most practical scenarios; in turn, noise degrades the measurement. Adjusting the bias signal amplitude to a slightly subthreshold operating regime, leads to a non-monotonic dependence of the (suitably defined) error on the noise intensity; at a critical noise intensity, the error is minimized. This phenomenon, reminiscent of the well-known Stochastic Resonance effect [1–4], appears to be most pronounced for subthreshold bias signals in the strongly nonlinear response regime. The results can be applied to a variety of nonlinear systems, including neurons, that operate in the time-domain.
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Blanes, Margarita, Javier de la Rubia, Juan J. Lahuerta, Juan D. Gonzalez, Paz Ribas, Carlos Solano, and Miguel A. Sanz. "Toxicity and Early Response after Single Daily Dose of Intravenous Busulfan and Melphalan as Conditioning Regimen for Autologous Stem Cell Transplantation in Patients with Multiple Myeloma." Blood 110, no. 11 (November 16, 2007): 4928. http://dx.doi.org/10.1182/blood.v110.11.4928.4928.
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Abstract Introduction: Conditioning regimen with oral busulfan (BU) and melphalan (MEL) for patients with multiple myeloma (MM) undergoing autologous transplant (ASCT) has been associated with a high incidence of liver complications, especially severe sinusoidal occlusive syndrome (SOS). Material and methods: We conducted the current study to assess the toxicity profile and outcomes associated with ASCT after intravenous (iv) BU-based conditioning in 45 patients (24 M/21 F; median age 60 years, range 34–71) with MM. Front-line chemotherapy consisted of VBMCP/VBAD (31cases), VAD (8 cases), and other regimens (6 cases). At transplant, 8 patients were in complete response (2 with negative immunofixation) 24 in partial response, 13 with other responses (6 with minor response, 5 had progressive disease, 1 stable disease, and 1 patient no evaluated). Median interval from diagnosis to transplant was 11 months (range 5–80). Conditioning regimen consisted of iv BU (3.2 mg/kg in a single daily dose, days −5 to −3) and MEL (140 mg/m2, day −2). In 39 patients this was the first ASCT and the remaining 6 had relapsed after a previous ASCT conditioned with MEL-based regimens. Results: Median number of CD34+ cells administered was 2.9 x10^6/kg (range 1–5.8). Hematopoietic recovery was fast with median (range) time to 0.5 PMN and 20 platelets x10^9/L of 12 (11–46) and 13 (9–64) days, respectively. The toxicity profile was favourable. Particularly, no case of SOS, commonly seen with the oral BU, has been reported. Mucositis was the non-hematopoietic toxicity most frequently seen (42 cases). Other toxicities observed were uncommon (gastrointestinal toxicity, 6 cases, increase of liver enzymes, 3 cases and mild cardiac failure, 1 case). Fever was observed in 38 patients: fever of unknown origin in 21 cases, microbiologically documented infection in 13 cases and clinically documented infection in the remaining 4 cases. Only 2 patients (4%) died due to transplant-related toxicity (one patient to pneumonia, day 51; the other patient to sepsis to Acinetobacter baumani, day 54). With a median follow-up of 18 months, 41 patients had been evaluated for response: 19 are in complete response (9 with negative immunofixation), 16 in partial response, 2 with minor response, 2 had progressive disease, and 2 transplant-related deaths. The 18 months actuarial overall and progression-free survival rates are 95±3% and 70±10%, respectively. Interestingly, in 19 patients significant improvement response was observed after transplant. Conclusions: These preliminary results show that iv BU-containing regimen for MM is associated with an acceptable toxicity profile and with a high anti-myeloma effect.
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Li, Xiuqi, Larisa Lozovatsky, Jackie A. Fretz, and Karin E. Finberg. "Bone Marrow Sinusoidal Endothelial Cells Are a Site of Fgf23 Upregulation in Iron Deficiency Anemia." Blood 138, Supplement 1 (November 5, 2021): 759. http://dx.doi.org/10.1182/blood-2021-153329.
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Abstract Iron deficiency anemia (IDA) has been identified as a potent stimulator of FGF23 (fibroblast growth factor 23), a phosphaturic hormone classically thought to be produced by bone-embedded osteocytes. Recently, both phlebotomy and erythropoietin administration have been shown to upregulate FGF23 production in bone marrow. However, the cell type(s) mediating FGF23 upregulation in states of perturbed erythropoiesis require further clarification. Tmprss6 -/- mice exhibit hepcidin elevation leading to systemic iron deficiency and iron-restricted anemia. We previously reported that Tmprss6-/- mice exhibit altered phosphate balance, elevated circulating FGF23, and Fgf23 mRNA upregulation in bone marrow but not cortical bone. Here, we clarify the sites of Fgf23 promoter activity in Tmprss6 -/- bone marrow using a reporter allele in which the enhanced green fluorescent protein (eGFP) coding sequence has been knocked into the endogenous Fgf23 locus. We generated Tmprss6 +/+,Tmprss6 +/-, and Tmprss6 -/- littermates of both sexes that carried either one (Fgf23 +/eGFP) or zero (Fgf23 +/+) copies of the reporter allele. Tmprss6-/- mice showed hyperhepcidinemia, hypoferremia, microcytic anemia, and tissue iron deficiency, which were not altered by heterozygous Fgf23 disruption (Figure 1A-C). By ELISA, Tmprss6-/- Fgf23 +/eGFP mice showed plasma levels of "total" FGF23 (intact, active hormone and C-terminal cleaved fragments) that remained markedly elevated compared to Tmprss6+/+ littermates (Figure 1D). Total FGF23 elevation in Tmprss6-/- Fgf23 +/eGFP mice was slightly less pronounced than Tmprss6-/- Fgf23 +/+ mice, suggesting an effect of Fgf23 gene dosage. In mice with 2 intact Fgf23 alleles, serum erythropoietin showed a strong linear correlation with plasma total FGF23. By confocal imaging, femurs of mice carrying the Fgf23 eGFP allele showed green fluorescence in vascular regions of the bone marrow but not in the bone cortex. Green fluorescence was more intense in Tmprss6-/- Fgf23+/eGFP mice than non-anemic controls. By flow cytometry of enzymatically digested bone marrow, we observed bright green fluorescence in a subset of endothelial cells (CD45 - Ter119 - CD31 +) exclusively in mice carrying the Fgf23 eGFP reporter allele (Figure 1E). The percentage of endothelial cells that were GFP bright was higher in Tmprss6-/- Fgf23 +/eGFP versus non-anemic mice. To clarify the endothelial cell subtype that expresses Fgf23, we mined published transcriptomic datasets from mice of normal iron balance and discovered higher Fgf23 mRNA in bone marrow sinusoidal endothelial cells compared to other bone marrow endothelial cell populations. Accordingly, we used anti-GFP immunohistochemistry in formalin-fixed bone marrow sections to assess Fgf23 eGFP reporter allele expression in the context of tissue architecture. Tmprss6-/- Fgf23 +/eGFP mice showed GFP expression in bone marrow sinusoidal endothelial cells, which was more intense than in non-anemic controls (Figure 1F). GFP reporter expression was also detected in rare cells of the thymus but not in liver, spleen, heart, muscle, or kidney. Collectively, our data reveal that bone marrow sinusoidal endothelial cells are a site of Fgf23 upregulation in chronic IDA. Because IDA in Tmprss6-/- mice results from pathologic hepcidin elevation, we also sought to determine if bone marrow sinusoidal endothelial cells are a site of Fgf23 upregulation in anemic mice with intact hepcidin regulation. We therefore subjected Fgf23 +/eGFP mice (with 2 intact Tmprss6 alleles) to a 500µl phlebotomy regimen (with saline volume replacement) known to induce marked anemia and hepcidin suppression. Compared to non-phlebotomized Fgf23 +/eGFP controls, phlebotomized Fgf23 +/eGFP mice showed severe anemia, elevated serum erythropoietin, and elevated plasma FGF23 18 hours after blood loss. Additionally, immunohistochemistry revealed more intense GFP expression in bone marrow sinusoidal endothelial cells of phlebotomized Fgf23 +/eGFP mice than non-phlebotomized controls. Taken together, our results show for the first time that bone marrow sinusoidal endothelial cells are a site of Fgf23 upregulation in both acute and chronic anemia. Given the serum erythropoietin elevation in both models, our findings suggest that erythropoietin may act directly or indirectly on sinusoidal endothelial cells to promote FGF23 production during anemia. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Chan, L., M. MacDonald, D. Chung, N. Hutchins, and A. Ooi. "Secondary motion in turbulent pipe flow with three-dimensional roughness." Journal of Fluid Mechanics 854 (August 31, 2018): 5–33. http://dx.doi.org/10.1017/jfm.2018.570.
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The occurrence of secondary flows is investigated for three-dimensional sinusoidal roughness where the wavelength and height of the roughness elements are systematically altered. The flow spanned from the transitionally rough regime up to the fully rough regime and the solidity of the roughness ranged from a wavy, sparse roughness to a dense roughness. Analysing the time-averaged velocity, secondary flows are observed in all of the cases, reflected in the coherent stress profile which is dominant in the vicinity of the roughness elements. The roughness sublayer, defined as the region where the coherent stress is non-zero, scales with the roughness wavelength when the roughness is geometrically scaled (proportional increase in both roughness height and wavelength) and when the wavelength increases at fixed roughness height. Premultiplied energy spectra of the streamwise velocity turbulent fluctuations show that energy is reorganised from the largest streamwise wavelengths to the shorter streamwise wavelengths. The peaks in the premultiplied spectra at the streamwise and spanwise wavelengths are correlated with the roughness wavelength in the fully rough regime. Current simulations show that the spanwise scale of roughness determines the occurrence of large-scale secondary flows.
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Kim, Jin-Soo, Sehhoon Park, Ki Hwan Kim, Jin Hyun Park, Won Kim, In Sil Choi, Yong Jin Jung, and Hwi Young Kim. "Changes in non-invasive liver fibrosis indices during chemotherapy: Potential marker for oxaliplatin-induced sinusoidal obstruction syndrome." Journal of Clinical Oncology 34, no. 4_suppl (February 1, 2016): 515. http://dx.doi.org/10.1200/jco.2016.34.4_suppl.515.
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515 Background: Oxaliplatin-based regimens are standard treatments for patients with colorectal (CRC) and advanced gastric cancer (AGC). However, the use of oxaliplatin sometimes results in hepatic sinusoidal obstruction syndrome (SOS). The aim of the study was to evaluate the utility of non-invasive liver fibrosis indices for monitoring oxaliplatin-induced hepatic SOS. We have reported a preliminary data in ASCO Annual Meeting 2014. Methods: From February 2004 to April 2014, patients with CRC or AGC who received oxaliplatin-based chemotherapy were studied. Possibility of SOS development was evaluated before and after the oxaliplatin exposure with splenic volume index (SVI). Four different non-invasive liver fibrosis indices were used for risk analysis: age-platelet index (API), AST to platelet ratio index (APRI), platelet to spleen ratio (PSR), Fibrosis-4 score (FIB-4). A prospective observation with serial elastrography is also ongoing. Results: A total of 275 patients were eligible for evaluation: 200 patients had CRC, and 75 patients had AGC. Using a cutoff of SVI increase ≥ 0.3, 113 patients (41.1%) were positive for hepatic SOS. Changes of indices were significantly correlated with SVI increase. Adjusted odds ratios for those indices were as follows: API = 1.16 (95% Confidential Interval [CI], 1.01 - 1.32; P = 0.032); APRI = 2.45 (95% CI, 1.30 - 4.63; P = 0.006); PSR = 0.69 (95% CI, 0.59 - 0.80; P < 0.001); FIB-4 = 1.37 (95% CI, 1.16 - 1.63; P < 0.001). Optimal cutoff-value with statistical significance were calculated and suggested. A total of 20 patients have been enrolled into the prospective observation until now. Comparison of elastographic changes and the indices in these patients will be presented. Conclusions: Changes of non-invasive liver fibrosis indices showed good correlation with SVI increase during oxaliplatin-based chemotherapy. These indices might be useful markers for monitoring of oxaliplatin-induced hepatic SOS. Serial monitoring of hepatic elastography could also be used for non-invasive monitoring of hepatic SOS.
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Kłosiński, Radosław. "The steady-state impedance operator of a linear periodically time-varying one-port network and its determination." International Journal of Applied Mathematics and Computer Science 19, no. 4 (December 1, 2009): 661–73. http://dx.doi.org/10.2478/v10006-009-0053-z.
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The steady-state impedance operator of a linear periodically time-varying one-port network and its determinationThe main subject of the paper is the description and determination of the impedance operator of a linear periodically timevarying (LPTV) one-port network in the steady-state. If the one-port network parameters and the supply vary periodically with the same period, the network reaches a periodic steady state. However, the sinusoidal supply may induce a non-sinusoidal voltage or current. It is impossible to describe such a phenomenon by means of one complex number. A periodically time-varying one-port network working in a steady-state regime can be described with a circular parametric operator. Within the domain of discrete time, such an operator takes the form of a matrix with real-valued entries. The circular parametric operator can be transformed into the frequency domain using a two-dimensional DFT. This description makes it possible to quantitatively assess LPTV system input and output harmonics aliasing. The paper also presents the derivation and the proof of convergence of an iteration scheme for the identification of circular parametric operators. The scheme may be used to determine the impedance of an LPTV one-port network. Some results of computer simulations are shown.
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Müser, Martin H. "Shear Thinning in the Prandtl Model and Its Relation to Generalized Newtonian Fluids." Lubricants 8, no. 4 (March 25, 2020): 38. http://dx.doi.org/10.3390/lubricants8040038.
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The Prandtl model is certainly the simplest and most generic microscopic model describing solid friction. It consists of a single, thermalized atom attached to a spring, which is dragged past a sinusoidal potential representing the surface energy corrugation of a counterface. While it was primarily introduced to rationalize how Coulomb’s friction law can arise from small-scale instabilities, Prandtl argued that his model also describes the shear thinning of liquids. Given its success regarding the interpretation of atomic-force-microscopy experiments, surprisingly little attention has been paid to the question how the Prandtl model relates to fluid rheology. Analyzing its Langevin and Brownian dynamics, we show that the Prandtl model produces friction–velocity relationships, which, converted to a dependence of effective (excess) viscosity on shear rate η ( γ ˙ ) , is strikingly similar to the Carreau–Yasuda (CY) relation, which is obeyed by many non-Newtonian liquids. The two dimensionless parameters in the CY relation are found to span a broad range of values. When thermal energy is small compared to the corrugation of the sinusoidal potential, the leading-order γ ˙ 2 corrections to the equilibrium viscosity only matter in the initial part of the cross-over from Stokes friction to the regime, where η obeys approximately a sublinear power law of 1 / γ ˙ .
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Lu, Q., A. Zhao, and L. Shen. "Preoperative transcatheter arterial chemoembolization (TACE) and chemotherapy for hepatic colorectal metastases: Impact on hepatic histology and postoperative outcome." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): e15090-e15090. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.e15090.
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e15090 Background: The objective was to evaluate the effect of preoperative administration of TACE and chemotherapy on hepatic injury and on postoperative outcome in patients with colorectal liver metastases (CRM) Methods: Seventy seven patients underwent hepatic resection for CRM between January 1999 and December 2007 were evaluated. Pathologic review of the non-tumorous liver was performed using established criteria for steatosis, steatohepatitis, and sinusoidal dilation. The effect of two different treatment and hepatotoxicity on postoperative outcome was analyzed. Results: 40 patients (51.9%) received no preoperative treatment, where 27 patients (35.0%) received preoperative chemotherapy, 10 patients (12.9%) performed TACE before resection. The median duration of TACE group was 4.5 months (range, 1–6 months), where the median duration of chemotherapy group was 5 cycles (range, 2–9 cycles). Chemotherapy regimen consisted of oxalipaltin plus FU (29.9%), or irinotecan plus FU (5.2%). On pathologic analysis, 36 patients (46.7%) had steatosis, 24 (31.1%) had sinusoidal dilation, and 8 (10.3%) had steatohepatitis. TACE was associated with steatosis, steatohepatosis and postoperative complication, when compared with no chemotherapy (all p<0.05).Among chemotherapy group,Oxaliplatin was associated with steatohepatitis compared with no preoperative treatment (13.0% v 0%, respectively; p<0.05). Irinotecan was associated with steatohepatitis compared with no preoperative treatment (50% v 0%, respectively; p=0.0006). Patients with preoperative chemotherapy had increased steatohepatitis compared with no treatment group (18.5% v 0%, respectively, p=0.0008), the postoperative morbility rate in preoperative chemotherapy (25.9%) was double that of the no-chemotherapy (12.5%), but this difference was not statistically significant (p=0.20). Preoperative chemotherapy was also not associated with 90-day mortality. Conclusions: Preoperative TACE treatment may cause pathological liver injury, and increase postoperative morbility after hepatic surgery. The standard preoperative chemotherapy regimen with Oxaliplatin or Irinotecan may increase steatohepatis. No significant financial relationships to disclose.
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Fernandes, Juliana F., Vanderson Rocha, Raphael Porcher, Benedicte Neven, Christophe Hue, Marli Tavela, Alain Fischer, Marco Antonio Zago, and Marina Cavazzana-Calvo. "Drug Metabolism Gene Polymorphisms and the Risk of Hepatic Sinusoidal Obstruction Syndrome in Children with Inherited Diseases Receiving Haematopoietic Stem Cell Transplantation." Blood 110, no. 11 (November 16, 2007): 1980. http://dx.doi.org/10.1182/blood.v110.11.1980.1980.
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Abstract Hepatic Sinusoidal Obstruction Syndrome (SOS) following high dose cytotoxic therapy remains a serious complication after heamatopoietic stem cell transplantation (HSCT). Genetic polymorphisms that interfere with metabolism of drugs used in conditioning regimens have been associated with SOS after HSCT. In order to study this association in children given a HSCT for inherited diseases of the heamatopoietic system we have analyzed candidate genes in 99 children: 35 who developed SOS and in 64 children who did not develop SOS; both groups were transplanted in the same center and matched for year of transplant (from 1998 to 2004). Four families of candidate genes were analyzed: P450 cytochrome [CYP2B6*2(C64T), *3(C777A), *4(A785G), *5(C1459T), *6(G516T)], Glutathione-S-Transferases [GSTM1 (null), GSTT1 (null), GSTP1 (A313G)], Methylenetetrahydrofolate reductase [MTHFR (C677T)] and Vitamin D receptor [VDR (ApaI, TaqI and BsmI)]. The most frequent diagnosis was severe combined immunodeficiency. The two groups had no statistical differences for gender, diagnosis, type of transplant and source of stem cells. Conditioning regimen consisted in busulfan and cyclophosphamide in 91% of SOS patients and 87% of non-SOS patients (p=ns). There was no statistical difference on the frequency of all gene polymorphisms studied in both groups of patients, except for the gene CYP2B6*2 (C64T). In fact, the mutant allele T (genotypes CT or TT) was present in 31% of SOS patients and 9% of remainders (p=0.01). CYP2B6 is known to play an important role in the metabolism of chemotherapeutic agents such as cyclophosphamide (CY). In conclusion, we found that the polymorphism in CYP2B6*2 allele of the P450 cytochrome family is more frequent in children with inherited diseases who have developed SOS after HSCT than in those who did not develop SOS. This finding may define better surveillance and prophylaxis of SOS for children with the mutant allele of CYP2B6*2 given a HSCT.
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Pakhomov, M. A., and V. I. Terekhov. "RANS Simulation of the Effect of Pulse Form on Fluid Flow and Convective Heat Transfer in an Intermittent Round Jet Impingement." Energies 13, no. 15 (August 4, 2020): 4025. http://dx.doi.org/10.3390/en13154025.
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The of effect pulse form (rectangular, sinusoidal and triangular) on the fluid flow and heat transfer of an intermittent jet impingement was studied numerically. It was shown in a non-steady-state jet, both an increase and decrease in heat transfer are possible compared with steady-state jet for all investigated pulse forms. For small distances between the pipe edge and obstacle (H/D ≤ 6) in the pulsed jet, heat transfer around the stagnation point increases with increasing pulse frequency, while for H/D > 8 an increase in frequency causes a heat transfer decrease. A growth in the Reynolds number causes a decrease in heat transfer, and data for all frequencies approach the steady-state flow regime. The numerical model is compared with the experimental results. Satisfactory agreement on the influence of the form and frequency of pulses on heat transfer for the pulsed jet on the obstacle surface is obtained.
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Caddell, Ryan James, Braydon Schaible, Zhenjun Ma, Elizabeth Dimaggio, Rebecca Tombleson, Claudio Anasetti, Ernesto Ayala, et al. "Fludarabine and Melphalan Results in Fewer Relapses Compared to Fludarabine and Targeted Busulfan in Patients Receiving Reduced Intensity Conditioning for AML and MDS." Blood 128, no. 22 (December 2, 2016): 3486. http://dx.doi.org/10.1182/blood.v128.22.3486.3486.
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Abstract Introduction: Fludarabine (Flu)-based conditioning regimens, combined with either melphalan (Mel) or intravenous busulfan (Bu), are often utilized in patients undergoing allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). While recent data supports that a myeloablative conditioning (MAC) strategy improves survival in patients who are able to tolerate this approach, the optimal regimen for patients elderly or unfit for MAC remains unclear. A single-center retrospective analysis was performed to evaluate outcomes in patients with AML or MDS deemed eligible only for reduced intensity regimens. Methods: Patients with AML and MDS who underwent peripheral blood mobilized allogeneic HCT at a single institution between January 2008 and December 2014 were identified. Of those, patients who received conditioning with either once-daily Bu (75-95 mg/m2) targeted to an area under the curve of 3500 µM*L/min and Flu 160 mg/m2 (Flu/Bu 3500) or Mel 140 mg/m2 plus Flu 120-160 mg/m2 (Flu/Mel) were evaluated and compared. All disease statuses (complete remission (CR), second CR, or with active disease) at time of HCT were included. Regimen toxicities, cumulative incidences of acute and chronic graft-versus-host disease (GVHD), non-relapse mortality (NRM), cumulative incidence of relapse (CIR), progression free survival (PFS), and overall survival (OS) were evaluated. Results: We identified 150 consecutive patients who received Flu/Bu 3500 (n=81) or Flu/Mel (n=69). Regimens were selected at physicians' discretion. The median ages for Flu/Bu 3500 and Flu/Mel were similar (66.9 (range, 48.2-75.9) and 65.8 (40.9-75.2) (p=0.14)). No differences were detected between the two groups with regard to recipient and donor gender, primary disease, donor type, recipient and donor cytomegalovirus (CMV) status, and Karnofsky performance status. Additionally, there were no differences between either groups in disease specific prognostic variables such as Disease Risk Index (Armand et al.), blast percentage at time of HCT, International Prognostic Scoring System (IPSS) and revised IPSS scoring in MDS patients, or AML cytogenetics at time of HCT. Patients receiving Flu/Mel had higher HCT-specific comorbidity index (HCT-CI, >3) when compared to Flu/Bu 3500 prior to transplantation (66.7% versus 46.9%, p=0.02). OS was similar between both arms (p=0.1) as was NRM (Hazard ratio (HR) 0.61 (CI, 0.34 - 1.1, p=0.1)) and PFS, HR 1.26 (CI, 0.83 - 1.94, p=0.2). However, CIR at 2 years post-allograft was significantly higher in the Flu/Bu 3500 arm, HR 2.54 (CI, 1.4 - 4.6, p=0.002) in comparison to Flu/Mel regimen (Figure 1). There was no difference detected in the cumulative incidences of either grades 2-4 acute GVHD, HR 1.00 (CI, 0.66 - 1.55, p=1.0), or grades 3-4 acute GVHD, HR 0.66 (CI, 0.27 - 1.57, p=0.3) between either conditioning regimen. The cumulative incidence of chronic GVHD was also similar, HR 1.27 (CI, 0.84 - 1.92, p=0.2). With regard to toxicity, diarrhea occurred more frequently in the Flu/Mel arm (p=0.0003) in the first 20 days following transplant. However, in the same period, mucositis occurred more frequently in the Flu/Bu 3500 arm (p=0.005). No differences were noted between the arms when assessing incidence of sinusoidal obstructive syndrome, diffuse alveolar hemorrhage, or thrombotic microangiopathy up to 90 days. Amongst patients receiving Flu/Mel, the most common cause of death was pneumonia or pulmonary failure (n=7) whereas the most common cause of death in the Flu/Bu 3500 arm was disease related (n=31). Conclusion: Flu/Mel resulted in a lower CIR at 2 years post-HCT compared to patients receiving Flu/Bu 3500 conditioning. Regarding toxicity, Flu/Mel produced more diarrhea but significantly less mucositis in comparison to Flu/Bu 3500; otherwise toxicity was comparable. Though there were no differences in OS and NRM between the two conditioning regimens, we speculate that the impact of the higher HCT-CI in the Flu/Mel arm may have contributed negatively to the lack of benefit in NRM and OS. Disclosures Locke: Kite: Membership on an entity's Board of Directors or advisory committees. Nishihori:Signal Genetics: Research Funding; Novartis: Research Funding. Fernandez:Chimerix: Honoraria; Otsuka: Honoraria; Sanofi: Speakers Bureau.
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Amit, Odelia, Yael Bar-On, Irit Avivi, Tsila Zuckerman, Galit Perets, Israel Henig, Itai Levi, Dana Yehudai-Ofir, Shimrit Ringelstein Harlev, and Ron Ram. "Radiation-Free Protocol for Patients with Acute Lymphoblastic Leukemia and Mixed Phenotype Acute Leukemia Undergoing Induction Chemotherapy and Allogeneic Hematopoietic Cell Transplantation - a Multicenter Historical Prospective Study." Blood 134, Supplement_1 (November 13, 2019): 5654. http://dx.doi.org/10.1182/blood-2019-128248.
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Introduction: Acute lymphoblastic leukemia (ALL) and mixed phenotype acute leukemia (MPAL) in adults are associated with a cure rate of only 20 and with a tendency for relapse to the CNS. Total body irradiation (TBI)-based high dose therapy and allogeneic hematopoietic cell transplantation (HCT) is a curative treatment for these patients, however, the median age for ALL in adults is 65 years and thus, majority of patients are not suitable candidates for high dose conditioning and HCT. Therefore, novel approaches are needed. Thiotepa is an alkylating lipophilic agent that result in achieving up to 100% cerebrospinal fluid levels and has been used in ablative regimens (total dose of 20 mg/kg), Christopoulos BBMT 2012. Methods: We aimed to test this regimen in patients with ALL/MPAL who were not eligible for a standard TBI-containing regimen and capped the thiotepa dose at 14 mg/kg (for patients given myeloablative regimen divided to 2 doses on Day -5 and -4) or at a dose of 10-12 mg/kg (in patients given a reduced intensity regimen). In addition patients were given BCNU at a dose of 400 mg/m^2 on Day -6 and fludarabine at a dose of 25 mg/m^2 on Day -6 to -4. We omitted entirely cranial irradiation, however Intrathecal (IT) therapy was allowed pretransplant (only) as per physician discretion. GVHD prophylaxis consisted of cycslosporine-methotrexate and ATG in cases of non-sibling donors. Results: Between July 2014 and June 2019, 22 patients from 3 centers in Israel were eligible for the protocol. Median follow up was 17 (range, 3-61) months. Median age at transplant was 51 (range, 22-68), Table. Majority of the patients (59%) had a CR1 with MRD negative disease . Ten patients (45%) were given a myeloablative regimen (>14 mg/kg of thiotepa) and 12 patients (55%) were given a reduced intensity regimen (10-12 mg/kg of thiotepa), majority (7 patients, 32%) because of age>60 years. Eight patients (36%) had a sibling donor, 12 patients (55%) had an unrelated donor and 2 (9%) had a 1 antigen-mismatch unrelated donor. GVHD prophylaxis consisted for all patients cyclosporine and a short course of methotrexate.Three patients (14%) developed sinusoidal obstruction syndrome (1 patient, severe). 7 patients (32%) had microbiology documented infections and 16 patients (73%) had grade 3-4 mucositis. All patients who survived (n=18, 82%) had a day 30-whole marrow donor chimerism > 96%. Cumulative incidences of grade 2-4 and grade 3-4 acute GVHD at day 200 were 51%(95% CI 35%-62%) and 11%(95% CI 5%-24%), respectively. Cumulative incidence of 2 year-moderate-severe chronic GVHD was 52% (95% CI 41%-74%). Relapse occurred in only 3 patients and all occurred within 4 months from HCT with a 2 year cumulative incidence of 17%(95% CI 12%-21%). Cumulative incidences of non-relapse mortality at 30 days, 3 months and 2 years after HCT were 15%(95% CI 8%-17%), 24%(95% CI 12%-32%) and 24%(95% CI 12%-32%), respectively. At time of data extraction 14 patients were alive. Cumulative Incidences of 2-year overall survival for CR1 patients with MRD negative disease and for non-CR1 patients with MRD negative disease at HCT were 70%(95% CI 61%-87%) and 62%(95% CI 50%-73%), respectively (p=.59), Figure. Factors associated in cox regression model with decreased overall survival were CNS involvement at diagnosis (p=.06, HR=2.24) and older age (p=.045, HR=1.5), while disease status at HCT, having a sibling donor, and intensity of conditioning were not predictive. Conclusions: This study shows that a thiotepa based regimen has substantial activity in patients with ALL, even in those who are older than 60 years and in patients intelligible to TBI. Reduced doses of thiotepa may have comparable efficacy and a lower toxicity profile when compared to higher doses and should be further investigated in this cohort of patients. Disclosures No relevant conflicts of interest to declare.
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Hardee, P. E., J. M. Stone, and J. Xu. "Theory and Simulation of Asymmetrically Perturbed Radiatively Cooled Jets." International Astronomical Union Colloquium 163 (1997): 575–79. http://dx.doi.org/10.1017/s0252921100043220.
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AbstractResults of a spatial stability analysis and of numerical simulations of a “slab” jet in which optically thin radiative cooling is dynamically important are presented. Two different cooling curves are used. Unstable Kelvin-Helmholtz modes are significantly different from the adiabatic limit, and the form of the cooling function strongly affects the results. The numerical simulations are in excellent agreement with the linear stability analysis. In the non-linear regime growth of the surface wave at low frequencies results in sinusoidal oscillation which can disrupt the jet, while non-linear body waves produce low amplitude wiggles within the jet that can result in shocks within the jet. In cooling jets, these shocks can produce dense knots and filaments of cooling gas within the jet, and weak shock “spurs” in the ambient gas. Acceleration of ambient gas can be produced by these “spurs”, or by rapid entrainment if the jet is disrupted. For parameters typical of protostellar jets perturbations with a period of < 100 yrs should excite body waves which produce internal shocks and small amplitude wiggles. The lack of large amplitude wiggles in most observed systems is consistent with the suggestion that jets arise from the inner regions (r < 1 AU) of accretion disks.
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Khattry, Navin, Reetu Jain, Ravi Thippeswamy, Adwaita Gore, Bharat Bhosale, Nandish Jeevangi, Sadhana Kannan, Amit Joshi, Reena Nair, and Tapan Saikia. "Comparison of Toxicity and Outcomes of BCNU-Containing Conditioning Regimens Vs LACE in Lymphoma Transplants: A Retrospective Multicenter Analysis." Blood 118, no. 21 (November 18, 2011): 2023. http://dx.doi.org/10.1182/blood.v118.21.2023.2023.
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Abstract Abstract 2023 Introduction: BCNU – containing regimens (CBV and BEAM) are commonly used in lymphoma transplants. LACE (lomustine-200 mg/ m2 × 1d, etoposide 1000mg/ m2 x1d, ara-c 2000 mg/m2x 2d and cyclophosphamide 1800mg/ m2 for 3d) is an effective and well tolerated regimen reported by few centers. We retrospectively compared the two types of conditioning regimens for toxicity, efficacy and outcome. Methods: One hundred and fifty five patients Hodgkin's disease (HD) and Non Hodgkin's lymphoma (NHL) with primary refractory or relapsed disease from August 1994- May 2011 were included in this study from 3 transplant centers in Mumbai, India. Seventy-nine patients received BEAM or CBV and 76 LACE. One-hundred two patients had HD (BEAM/CBV-50, LACE-52) while 52 had NHL (BEAM/CBV-28, LACE- 24).Stem cell source was peripheral blood (PBSC) in all but one patient in LACE group and 68 patients in BEAM/CBV group. Oral mucositis was graded by WHO criteria while all other toxicities by common toxicity criteria version-3. Total Parenteral Nutrition (TPN) was used in patients with poor oral intake. Neutrophil engraftment (NE) was defined as first day of ANC > 0.5 × 109/L and platelet engraftment (PE) as first of seven days of unsupported platelet count > 20 × 109/L. Sinusoidal Obstruction Syndrome (SOS) of the liver was recorded according to Seattle criteria. Categorical data was analyzed using chi-square while continuous data with Mann Whitney Test. Overall survival (OS) and progression-free survival (PFS) was analyzed using Kaplan Meier survival analysis. Results: The median age at transplant was comparable (BEAM/CBV-25 year, LACE-23 year). Eleven patients in BEAM/CBV group had chemotherapy refractory disease compared to 6 in LACE at the time of transplant (P=0.106).The median serum albumin level (BEAM/CBV -3.9 gm/dl, LACE- 3.9 gm/dl) at the time of diagnosis were comparable. Incidence of grade 3 and 4 oral mucositis was higher in BEAM/CBV compared to LACE group (45 % vs 10%; P<0.001). Thirty-six (47%) patients in LACE group did not develop any grade of oral mucositis (P=0.001).The maximum grade and duration of diarrhea were comparable. More patients in BEAM/CBV group required parenteral nutrition (66% vs 33%; P=0.00004) and for longer duration (10 vs 9 days; P=0.003). No patient in LACE developed SOS compared to 5 in BEAM/CBV (P=0.05). Transplant related mortality was higher in BEAM/CBV (16 % vs 6%; P=0.063). The median CD 34 cell count of the stem cell graft was comparable (BEAM/CBV- 2.6 × 106/kg, LACE-5.9 × 106/kg; P=0.259), however more patients in the LACE group received PBSC grafts (BEAM/CBV-86%, LACE-98%; P=0.01). The median days to neutrophil engraftment (10 vs 11; P=0.014) and platelet engraftment (13 vs 15; P=0.006) were shorter in LACE. Median duration of hospitalization was less in LACE (3.3 vs 4 weeks P=0.016). At 2.5 years, OS (BEAM/CBV −58.5%, LACE −71%) and PFS (BEAM/CBV-50%, LACE-33%) were comparable, though in HD subgroup, OS was superior with LACE (BEAM-58%, LACE-85%; P=0.028). Conclusion: In our retrospective multicenter analysis LACE is a better tolerated regimen with lesser toxicity, earlier engraftment and comparable survival rates. Randomized trials comparing it with BCNU- containing regimens are needed. Disclosures: No relevant conflicts of interest to declare.
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Kameoka, Yoshihiro, Naoto Takahashi, Kenichi Ishizawa, Kazunori Murai, Yuichi Kato, Hideyoshi Noji, Jugo Ito, et al. "Safety, Feasibility and Efficacy of High Dose Ranimustine (MCNU), Carboplatin, Etoposide, and Cyclophosphamide (MCVC) Therapy Followed by Autologous Stem Cell Transplantation for Malignant Lymphoma." Blood 116, no. 21 (November 19, 2010): 4588. http://dx.doi.org/10.1182/blood.v116.21.4588.4588.
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Abstract Abstract 4588 Background: High-dose chemotherapy (HDCT) followed by autologous hematopoietic stem cell transplantation (auto-HSCT) has been shown to be appropriate approach compared with standard salvage therapy in patients with chemo-sensitive relapsed/refractory malignant lymphoma. Although a regimen consisting of high dose ranimustine (MCNU), carboplatin, etoposide and cyclophosphamide (MCVC) is widely used in clinical practice in Japan as HDCT followed by auto-HSCT for refractory malignant lymphoma, there have been few studies that tried to clarify the details of this therapy. We have conducted a multicenter prospective study involving 7 centers in Japan in order to investigate safety, feasibility and efficacy of MCVC regimen followed by auto-HSCT. Method: This study was carried out according to the principles set out in the Declaration of Helsinki, 1975, and the protocol and informed-consent forms were approved by the institutional review board before the initiation of the study. All patients provided written informed consent. Between July 2007 and June 2009, 30 patients with relapsed/refractory/poor-risk non-Hodgkin lymphoma (NHL n=27) or Hodgkin lymphoma (HD n=3) were uniformly treated with MCVC regimens and underwent auto-HSCT as follows: ranimustine (MCNU) 200mg/m2 i.v. on day-8 and -3 (total dose 400 mg/m2), carboplatin 300mg/m2 i.v. on day-7 to -4 (total dose 1200mg/m2), etoposide (VP-16) 500mg/m2 i.v. on day -6 to -4 (total dose 1500 mg/m2), and cyclophosphamide 50mg/kg i.v. on day-3 and -2 (total dose 100mg/kg). Hematopoietic stem cells were reinfused on day 0 and G-CSF administrated until hematological recovery. Result and discussion: Median age at transplantation was 51 (range, 18–62). Four (13%) of these patients were older than 60 years. Diffuse large B-cell lymphoma was the most main histologic subtype in these patients (43%). At transplantation, 16 (53%) were in CR and the others showed PR (n=12, 40%) or PD (n=2, 7%). Median number of CD34+ cells reinfused was 4.8 × 106/kg (range, 2.0–11.2 × 106/kg). All patients achieved prompt engraftment after auto-SCT; that is, the median numbers of days to achieve engraftment of neutrophils (>500/μ l) and platelets (>20000/μ l) were 10 and 13, respectively. The median amounts of red blood cell and platelet transfusions after auto-HSCT were 4 units and 50 units, respectively. The major toxicities (>50% in patients) were appetite loss (all grade 97%, grade 3/4 70%), febrile neutropenia (grade 3/4 70%), nausea/vomiting (all grade 80%, grade 3/4 56%), diarrhea (all grade 77%, grade 3/4 17%), alopecia (all grade 63%) and mucositis (50%). Treatment-related mortality (TRM) was 3.3% with one death caused by sinusoidal obstructive syndrome. With median post-transplantation follow up times of 15 months, median over all survival was not reached and median event-free survival was 18.9 months (95% CI, 14.3–23.7 months). These data suggested that the time of bone marrow recovery from transplantation and the incidence of febrile neutropenia of the MCVC were similar to that of the BEAM and BEAC. The incidence of nausea/vomiting, diarrhea and mucositis seemed to be more frequent with the MCVC than the BEAC and BEAM, and the incidence of TRM of MCVC seems to be lower than that of the BEAC and BEAM regimens. Conclusion: These outcomes suggest that the MCVC regimen followed by auto-SCT is a feasible, tolerable and effective therapy for relapsed/refractory malignant lymphoma. Disclosures: No relevant conflicts of interest to declare.
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Eder, Sandra, Myriam Labopin, Jurgen Finke, Donald W. Bunjes, Attilio Olivieri, Stella Santarone, Alessandro Rambaldi, et al. "Safety and Efficacy of Thiotepa-Based Conditioning Therapy for Allogeneic Transplantation in Acute Myeloid Leukemia - a Survey from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation." Blood 124, no. 21 (December 6, 2014): 3895. http://dx.doi.org/10.1182/blood.v124.21.3895.3895.
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Abstract Background Thiotepa (TTP) is an alkylating compound with an antineoplastic activity that has been used since the early nineties. However, few studies focused on the analysis of the benefit of TTP in the pre-allogeneic hematopoietic stem cell transplantation (HSCT) conditioning in a specific disease category. Beside its antineoplastic activity, TTP has immunosuppressive properties and the ability to penetrate the blood-brain barrier in conjunction with a good toxicity profile that makes it an attractive compound to use in the transplant setting. Therefore, the aim of the current analysis was to investigate the potential impact of TTP as part of the conditioning therapy for acute myeloid leukemia (AML) patients in first complete remission (CR1) and beyond. Methods This retrospective multicentre study was performed by the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Inclusion criteria were adults with AML who received TTP as part of the conditioning regimen for first allogeneic HSCT between 1992 and 2012 (median 2008). Results A total of 310 patients with AML (13% secondary) were identified. Median age was 46.5 years; 54% were males and 46% females. 14% of the patients received a previous autologous HSCT. Disease status at HSCT was CR1 in 50%, CR2+ in 23.5%, while 26.5% of the patients had an advanced disease at time of transplant. Cytogenetics was good, intermediate and poor in 8%, 69% and 14%, respectively. Transplantation was performed from an haploidentical donor (35%), matched sibling donor (27%), an unrelated donor (20%) or cord blood (18%). Seventy percent of patients received a myeloablative and 30% a reduced-intensity conditioning regimen. TTP was mostly combined with fludarabine (43%), fludarabine + busulfan (32%) and cyclophosphamide (25%). Median dose of TTP was 10 mg/kg (IQR: 10 – 16). Neutrophil engraftment was 92±3% at a median day of 16 (range, 8 – 38). Mucositis (all grades) occurred in 46.8% of patients with a median day of onset at day 3 after HSCT. Incidence of sinusoidal obstruction syndrome (SOS) was low: 4.3% of patients developed SOS with a median day of onset at day 8 post-transplant. Non-relapse mortality after 100 days was 19±2%. Incidence of acute GvHD (Grade> II) was 26% at day 100, while chronic GvHD occurred in 28±3% at 3 years (56% with limited and 44% with extensive disease). 204 patients died. Main cause of death was infection (35%), original disease (31%), GvHD (10%), interstitial pneumonia (6%), SOS (2%) and other transplant related causes (15%). Two patients died due to a secondary malignancy (1%). With a median follow-up of 37 months, non-relapse mortality at 3 years was 38±4%, 50±6% and 45±6% for patients in CR1, CR2+ and advanced disease, respectively (p=0.10). Relapse incidence at 3 years was 20±3% (CR1), 31±5% (CR2+) and 41±5% (advanced disease; p=0.002). Three-year leukemia-free survival and overall survival were 41±1% and 46±4% (CR1), 20±10% and 28±5% (CR2+) and 14±4% and 14±4% (advanced disease), respectively (p<10-4 for both, leukemia-free and overall survival). Conclusion This large survey suggests that TTP-based conditioning therapy in AML is feasible and effective, with main outcomes being comparable to results achieved with other regimens. Of note, side effects incidence (e.g. SOS and mucositis) is relatively low. The latter might explain the increased use of this agent in conditioning regimens prior to allogeneic HSCT. Disclosures Mohty: Riemser : Research Funding.
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Zhang, Yudong, Aiguo Xu, Feng Chen, Chuandong Lin, and Zon-Han Wei. "Non-equilibrium characteristics of mass and heat transfers in the slip flow." AIP Advances 12, no. 3 (March 1, 2022): 035347. http://dx.doi.org/10.1063/5.0086400.
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Slip flow is a common phenomenon in micro-/nano-electromechanical systems. It is well known that the mass and heat transfers in slip flow show many unique behaviors, such as the velocity slip and temperature jump near the wall. However, the kinetic understanding of slip flow is still an open problem. This paper first clarifies that the Thermodynamic Non-Equilibrium (TNE) flows can be roughly classified into two categories: near-wall TNE flows and TNE flows away from the wall. The origins of TNE in the two cases are significantly different. For the former, the TNE mainly results from the fluid–wall interaction; for the latter, the TNE is primarily due to the considerable (local) thermodynamic relaxation time. Therefore, the kinetic modeling methods for the two kinds of TNE flows are significantly different. Based on the Discrete Boltzmann Modeling (DBM) method, the non-equilibrium characteristics of mass and heat transfers in slip flow are demonstrated and investigated. The method is solidly verified by comparing with analytic solutions and experimental data. In pressure-driven flow, the DBM results are consistent with experimental data for the Knudsen number up to 0.5. It is verified that, in the slip flow regime, the linear constitutive relations with standard viscous or heat conduction coefficients are no longer applicable near the wall. For the Knudsen layer problem, it is interesting to find that a heat flux (viscous stress) component in the velocity (temperature) Knudsen layer approximates a hyperbolic sinusoidal distribution. The findings enrich the insights into the non-equilibrium characteristics of mass and heat transfers at micro-/nano-scales.
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Kuranda, Klaudia, Christine Weisshaar, Yifeng Chen, Corinne Smith, Heena Beck, Kristen Kahle, and Federico Mingozzi. "Tocilizumab As a Novel Immunomodulatory Regimen for Hemophilia Gene Therapy." Blood 138, Supplement 1 (November 5, 2021): 1853. http://dx.doi.org/10.1182/blood-2021-147511.
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Abstract Hemophilia is an X-linked bleeding disorder typically resulting in deficiency of factor VIII (FVIII) or factor IX (FIX) due to mutations in the F8 or F9 genes, respectively. Data from clinical trials have shown that the investigational delivery of functional F8 or F9 gene by recombinant adeno-associated virus (AAV) to hepatocytes can substantially eliminate the need for infusions of clotting factor in hemophilia patients. Despite major advances, the durability and redosing of these investigational gene therapies have been limited by the host immune response against the AAV capsid (Verdera et al. Mol Ther 2020). Currently, an oral corticosteroid, prednisone, is commonly used to prevent cytotoxic T cells from killing AAV-transduced hepatocytes and to sustain the production of transgenic clotting factor. However, in some instances, transgene expression was lost despite prednisone administration and prolonged use of prednisone can be associated with adverse effects. Previously, we demonstrated that the anti-capsid humoral response depends on interleukin 6 (IL-6) secretion from human monocyte-related dendritic cells (Kuranda et al. JCI 2018). IL-6 signaling in response to AAV was also observed in human non-parenchymal liver cells in vitro, animal gene transfer models and AAV-based gene therapy trial for hemophilia B (Konkle et al. Blood 2021). Here, we investigated the effects of the IL-6 signaling blockade as a possible targeted approach to modulate AAV vector immunogenicity in hemophilia gene therapy using a non-human primate (NHP) model. Spk100 AAV capsid was used to deliver the human F9 gene. To prevent IL-6 signaling, we used a monoclonal antibody, tocilizumab (TCZ), which blocks the IL-6 receptor. TCZ is currently approved for use in several forms of arthritis and cytokine release syndrome. Ten male cynomolgus monkeys received an intravenous injection of Spk100-hFIX vector (4x10 12 vg/kg) and 5 of those animals received a single dose of TCZ (8 mg/kg) the day prior to vector administration and were monitored for 13 weeks. As assessed by an array of clinical and anatomic pathology parameters, the investigational use of gene therapy combined with prophylactic TCZ administration was safe and well-tolerated. TCZ did not interfere with vector biodistribution, liver transduction or the transgenic FIX production. Spk100-hFIX alone modestly increased IL-6 secretion from NHP peripheral blood mononuclear cells (PBMC) in vitro but, following the vector infusion in animals, plasma IL-6 levels did not change significantly. Overall, cytokine secretion in response to Spk100 capsid and hFIX protein was lower in PBMCs isolated from TCZ-treated animals compared to cells obtained from control animals. As expected, animals administered Spk100-hFIX alone developed anti-capsid antibodies. The administration of TCZ was associated with a lower level of anti-Spk100 IgM, IgG and neutralizing antibodies (NAb). While the blockade of IL-6 signaling was effective for about for 14 days post-vector infusion, the lower level of anti-Spk100 antibodies persisted for the entire study duration. In the TCZ group, 4 out of 5 animals had NAb titers equal to or below 1:10, theoretically compatible with vector readministration. In contrast, 4 out of 5 animals in the control group developed high titer NAbs following vector infusion. Importantly, TCZ reduced the detection of the capsid-specific TNFα-positive T cells that were observed in animals after vector infusion. Finally, livers from sacrificed animals were used to prepare liver non-parenchymal cells for ex vivo phenotyping. Compared to the control animals, liver-resident immune cells from the TCZ-treated group had increased basal IL-10 secretion, while liver sinusoidal endothelial cells (albumin-CD45-CD31+CD146+MHCII+) had lower surface levels of MHC class II molecules, suggesting an anti-inflammatory milieu in the TCZ-treated livers. Our results show that short-term prophylactic blockade of IL-6 signaling was safely used in NHPs and has the potential to reduce immune responses commonly observed post AAV vector infusion. These results support the continued investigation of tocilizumab as a targeted immunomodulatory regimen in liver gene therapy for hemophilia. Disclosures Kuranda: Spark Therapeutics: Current Employment. Weisshaar: Spark Therapeutics: Current Employment. Chen: Spark Therapeutics: Ended employment in the past 24 months. Smith: Spark Therapeutics: Current Employment. Beck: Spark Therapeutics: Current Employment. Kahle: Spark Therapeutics: Current Employment. Mingozzi: Spark Therapeutics: Current Employment.
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Popat, Uday R., Rohtesh S. Mehta, Roland Bassett, Amin M. Alousi, Gheath Alatrash, Qaiser Bashir, Chitra Hosing, et al. "Optimizing Myeloablative Fractionated Busulfan, Fludarabine and Thiotepa Regimen: Results of Two Parallel Cohorts in a Phase 2 Prospective Clinical Trial." Blood 138, Supplement 1 (November 5, 2021): 1802. http://dx.doi.org/10.1182/blood-2021-146655.
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Abstract Background: Myeloablative conditioning can be given safely to older patients by simply administering busulfan (Bu) over a longer period (fractionated (f)-Bu) with fludarabine (Flu) than the standard four-day regimen. (Popat et al Lancet Haematology 2018). We added thiotepa (Thio) to this f-Bu/Flu regimen in patients with haploidentical (haplo) donors to promote engraftment and to reduce relapse. With encouraging results, Thio was then added in matched unrelated (MUD) and sibling (MSD) donor recipients also. However, the optimal doses of Thio and Bu were undefined. To further optimize the regimen, we tested two different f-Bu/Flu/Thio regimens in parallel prospective cohorts: (a) higher dose Bu with lower dose Thio, and (b) lower dose Bu with a higher dose Thio. Patients were enrolled on these cohorts based on age and co-morbidity index (HCT-CI). Herein, we report on the safety and preliminary efficacy of these regimens (NCT02861417). Methods: Patients <60 years with HCT-CI <3, or >60 years with HCT-CI <2 received IV f-Bu to target an area under the concentration vs time curve (AUC) of 20,000 ± 12% μmol.min with Thio 2.5 mg/kg (Bu20K/Thio2.5; Cohort 1). Patients <60 years with an HCT-CI >3, or >60 years with HCT-CI >2, or >70 years irrespective of HCT-CI received f-BU to target AUC of 16,000 with Thio 5mg/kg (Bu16K/Thio5; Cohort 2). In both cohorts, the first two doses of Bu (80 mg/m2 IV each) were given as outpatient on days -20 and -13. The last four Bu doses were given as inpatient following each dose of Flu 40 mg/m2 on days -6 through -3. Thio was given on day -7. GVHD prophylaxis was post-transplant cyclophosphamide (PTCy) 50mg/kg on days 3 and 4, tacrolimus and MMF. Results: 66 patients were enrolled - 25 in cohort 1 and 41 in cohort 2, with a median age 60 years (range, 22-69) vs 62 years (range, 30-74), respectively (P=0.14). Diagnoses were AML/MDS (64% vs 54%), CML/MPD (24% vs 22%), ALL (12% vs 22%) and 1 myeloma; P=0.24. Most had intermediate disease risk index (80% vs 73%, P=0.57); median HCT-CI was 1 (range, 0-6) vs 3 (range, 0-9); P<0.0001. Donor was haplo (60% vs 19%), MUD (24% vs 54%) or MSD (16% vs 27%); P=0.002; BM graft was used in 56% vs 27%; p=0.02, respectively, in cohorts 1 and 2. The median follow-up among survivors was 18.7 months. Primary graft failure occurred in 1 patient in cohort 1 and none in cohort 2. The median time to neutrophil engraftment was 17.5 days (range, 14-26) vs 18 days (range, 12-26); P=0.12, respectively; platelet engraftment > 20K was 30 days in both groups; P=0.75. Median donor chimerism at day 30 was 100% in both groups. The incidence of acute GVHD grade III-IV was 4% vs 5%; P=0.88 at day 100; extensive chronic GVHD at 1 year was 13% vs 10%; P=0.83. At 1-year overall survival was 72% vs 78%; P=0.95; relapse was 12% each; non-relapse mortality was 20% vs 17%; P=0.97 [Table 1, Fig 1]. Common grade >3 toxicities were neutropenic fever (64% vs 42%; P=0.13), bacterial infection (44% vs 34%; P=0.45), nausea (12% vs 2%; P=0.15), mucositis (8% vs 5%; P=0.63), pneumonitis (12% vs 7%; P=0.67), hemorrhagic cystitis (8% vs 5%) and sinusoidal obstructive syndrome (8% vs 2.4%). Conclusion: In this population of older patients and/or high co-morbidities, both myeloablative regimens with f-Bu/Flu with thiotepa and PTCy were well tolerated and led to low NRM, low risk of relapse and encouraging survival. Although both regimens led to similar outcomes, the f-Bu/Flu/Thio regimen with Bu16K and thiotepa 5 mg/kg dose may be preferred as this was used in patients who were older and/or had high co-morbidities. Figure 1 Figure 1. Disclosures Popat: Bayer: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding. Mehta: CSLBehring: Research Funding; Kadmon: Research Funding; Syndax: Research Funding; Incyte: Research Funding. Hosing: Nkarta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Rezvani: Caribou: Other: Scientific Advisory Board; Virogin: Other: Scientific Advisory Board ; AvengeBio: Other: Scientific Advisory Board ; GSK: Other: Scientific Advisory Board ; Bayer: Other: Scientific Advisory Board ; Navan Technologies: Other: Scientific Advisory Board; GemoAb: Other: Scientific Advisory Board ; Takeda: Other: License agreement and research agreement, Patents & Royalties; Pharmacyclics: Other: Educational grant, Research Funding; Affimed: Other: License agreement and research agreement; education grant, Patents & Royalties, Research Funding. Qazilbash: Oncopeptides: Other: Advisory Board; Janssen: Research Funding; Bristol-Myers Squibb: Other: Advisory Board; NexImmune: Research Funding; Amgen: Research Funding; Angiocrine: Research Funding; Biolline: Research Funding. Shpall: Affimed: Patents & Royalties; Adaptimmune: Consultancy; Novartis: Consultancy; Magenta: Consultancy; Magenta: Honoraria; Axio: Consultancy; Takeda: Patents & Royalties; Navan: Consultancy; Novartis: Honoraria; Bayer HealthCare Pharmaceuticals: Honoraria.
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Acharyya, Aritra, Jit Chakraborty, Kausik Das, Subir Datta, Pritam De, Suranjana Banerjee, and J. P. Banerjee. "Large-signal characterization of DDR silicon IMPATTs operating up to 0.5 THz." International Journal of Microwave and Wireless Technologies 5, no. 5 (June 11, 2013): 567–78. http://dx.doi.org/10.1017/s1759078713000597.
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Large-signal (L-S) characterization of double-drift region (DDR) impact avalanche transit time (IMPATT) devices based on silicon designed to operate at different millimeter-wave (mm-wave) and terahertz (THz) frequencies up to 0.5 THz is carried out in this paper using an L-S simulation method developed by the authors based on non-sinusoidal voltage excitation (NSVE) model. L-S simulation results show that the device is capable of delivering peak RF power of 657.64 mW with 8.25% conversion efficiency at 94 GHz for 50% voltage modulation; whereas RF power output and efficiency reduce to 89.61 mW and 2.22% respectively at 0.5 THz for same voltage modulation. Effect of parasitic series resistance on the L-S properties of DDR Si IMPATTs is also investigated, which shows that the decrease in RF power output and conversion efficiency of the device due to series resistance is more pronounced at higher frequencies especially at the THz regime. The NSVE L-S simulation results are compared with well established double-iterative field maximum (DEFM) small-signal (S-S) simulation results and finally both are compared with the experimental results. The comparative study shows that the proposed NSVE L-S simulation results are in closer agreement with experimental results as compared to those of DEFM S-S simulation.
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Niebuhr, Peter, and Mike Sieder. "High-cycle fatigue behaviour of a timber-to-timber connection with self-tapping screws under lateral loading." European Journal of Wood and Wood Products 79, no. 4 (April 17, 2021): 785–96. http://dx.doi.org/10.1007/s00107-021-01699-x.
Full textAbstract:
AbstractThe high-cycle fatigue behaviour of a timber-to-timber connection with self-tapping screws is examined with the fasteners under bending due to their alignment lateral to the load direction. The cyclic tests were carried out with a sinusoidal non-reversed load ($$R=0.1$$ R = 0.1 ) with a loading frequency of 5 Hz. The examined connection is designed for the quasistatic failure mechanism with two plastic hinges per shear plane according to Johansen’s theory (European Yield Model), which is mirrored in the observed fatigue failure. Based on 30 cyclic tests on four nominal stress levels $$\left( S=\left\{ 0.47,\;0.41,\;0.31,\;0.20 \right\} \right) $$ S = 0.47 , 0.41 , 0.31 , 0.20 in the finite-life regime the respective Wöhler-curve is obtained, showing high conformity with the test data due to a consideration of the specific density of the individual specimens. It is shown that the examined fasteners show a superior fatigue behaviour under bending compared to axial loading. A simple safe-side approach for the application of Wöhler-curves for axial loading of threaded fasteners to the present case of fastener bending is proposed, extending the field of possible applications for the results of existing and future studies of the behaviour under axial loading.
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Khan, Saadbin, and Balaji Jayaraman. "Statistical Structure and Deviations from Equilibrium in Wavy Channel Turbulence." Fluids 4, no. 3 (August 27, 2019): 161. http://dx.doi.org/10.3390/fluids4030161.
Full textAbstract:
The structure of turbulent flow over non-flat surfaces is a topic of major interest in practical applications in both engineering and geophysical settings. A lot of work has been done in the fully rough regime at high Reynolds numbers where the effect on the outer layer turbulence structure and the resulting friction drag is well documented. It turns out that surface topology plays a significant role on the flow drag especially in the transitional roughness regime and therefore, is hard to characterize. Survey of literature shows that roughness function depends on the interaction of roughness height, flow Reynolds number, and topology shape. In addition, if the surface topology contains large enough scales then it can impact the outer layer dynamics and in turn modulate the total frictional force. Therefore, it is important to understand the mechanisms underlying drag increase from systematically varied surface undulations in order to better interpret quantifications based on mean statistics such as roughness function. In this study, we explore the mechanisms that modulate the turbulence structure over a two-dimensional (2D) sinusoidal wavy surface with a fixed amplitude, but varying slopes that are sufficiently small to generate only intermittent flow separation. To accomplish this, we perform a set of highly resolved direct numerical simulations (DNS) to model the turbulent flow between two infinitely wide 2D wavy plates at a friction Reynolds number, R e τ = 180 , which represents modest scale separation. We pursue two different but related flavors of analysis. The first one adopts a roughness characterization flavor of such wavy surfaces. The second one focuses on understanding the nonequilibrium near-surface turbulence structure and their impact on roughness characterization. Analysis of the different statistical quantifications show strong dependence on wave slope for the roughness function indicating drag increase due to enhanced turbulent stresses resulting from increased production of vertical velocity variance from the surface undulations.
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Layland, J., I. S. Young, and J. D. Altringham. "The length dependence of work production in rat papillary muscles in vitro." Journal of Experimental Biology 198, no. 12 (December 1, 1995): 2491–99. http://dx.doi.org/10.1242/jeb.198.12.2491.
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The influence of length on work production was investigated for rat papillary muscles using the work loop technique. Active and passive length-force relationships were first determined under isometric conditions and the length for maximum force production (Lmax) was derived. Starting from different lengths within the physiological range, a series of work loops was generated using the stimulation phase shift, strain amplitude and cycle frequency previously found to be optimal for power output at 37 degrees C. The relationship between muscle length and net work was used to determine the length at which work output was maximal (Lopt). In order to examine the dynamic passive properties of the muscles, unstimulated muscles were subjected to the same regime of sinusoidal oscillation as used for the active loops. From the hysteresis loops, lengthening work (work done to extend the passive muscle), passive shortening work (work returned during shortening) and net energy loss (hysteresis) could be measured. The decline in net work production at lengths greater than 95% Lmax could largely be attributed to the rapid and non-linear increase in muscle stiffness and the increase in net energy loss over this range of lengths. The physiological significance of the length-work relationship is considered and the mechanical properties of active and passive papillary muscles are discussed with reference to sarcomere length and cardiac muscle ultrastructure.
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Samtaney, Ravi, and Norman J. Zabusky. "Circulation deposition on shock-accelerated planar and curved density-stratified interfaces: models and scaling laws." Journal of Fluid Mechanics 269 (June 25, 1994): 45–78. http://dx.doi.org/10.1017/s0022112094001485.
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Vorticity is deposited baroclinically by shock waves on density inhomogeneities. In two dimenslons, the circulation deposited on a planar interface may be derived analytically using shock polar analysis provided the shock refraction is regular. We present analytical expressions for Γ′, the circulation deposited per unit length of the unshocked planar interface, within and beyond the regular refraction regime. To lowest order, Γ′ scales as \[ \Gamma^\prime\propto (1-\eta^{-\frac{1}{2}})(\sin\alpha)(1+M^{-1}+2M^{-2})(M-1)(\gamma^{\frac{1}{2}}/\gamma + 1)\] where M is the Mach number of the incident shock, η is the density ratio of the gases across the interface, α is the angle between the shock and the interface and γ is the ratio of specific heats for both gases. For α ≤ 30°, the error in this approximation is less than 10% for 1.0 < M ≤ 1.32 for all η > 1, and 5.8 ≤ η ≤ 32.6 for all M. We validate our results by quantification of direct numerical simulations of the compressible Euler equations with a second-order Godunov code.We generalize the results for total circulation on non-planar (sinusoidal and circular) interfaces. For the circular bubble case, we introduce a ‘near-normality’ ansatz and obtain a model for total circulation on the bubble surface that agrees well with results of direct numerical simulations. A comparison with other models in the literature is presented.
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Xie, Yi-Chao, Ping Wei, and Ke-Qing Xia. "Dynamics of the large-scale circulation in high-Prandtl-number turbulent thermal convection." Journal of Fluid Mechanics 717 (February 1, 2013): 322–46. http://dx.doi.org/10.1017/jfm.2012.574.
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AbstractWe report experimental investigations of the dynamics of the large-scale circulation (LSC) in turbulent Rayleigh–Bénard convection at high Prandtl number $\mathit{Pr}= 19. 4$ (and also $\mathit{Pr}= 7. 8$) and Rayleigh number $\mathit{Ra}$ varying from $8. 3\times 1{0}^{8} $ to $2. 9\times 1{0}^{11} $ in a cylindrical convection cell with aspect ratio unity. The dynamics of the LSC is measured using the multithermal probe technique. Both the sinusoidal-fitting (SF) and the temperature-extrema-extraction (TEE) methods are used to analyse the properties of the LSC. It is found that the LSC in high-$\mathit{Pr}$ regime remains a single-roll structure. The azimuthal motion of the LSC is a diffusive process, which is the same as those for $\mathit{Pr}$ around 1. However, the azimuthal diffusion of the LSC, characterized by the angular speed $\Omega $ is almost two orders of magnitude smaller when compared with that in water. The non-dimensional time-averaged amplitude of the angular speed $\langle \vert \Omega \vert \rangle {T}_{d} $ (${T}_{d} = {L}^{2} / \kappa $ is the thermal diffusion time) of the LSC at the mid-height of the convection cell increases with $\mathit{Ra}$ as a power law, which is $\langle \vert \Omega \vert \rangle {T}_{d} \propto {\mathit{Ra}}^{0. 36\pm 0. 01} $. The $\mathit{Re}$ number based on the oscillation frequency of the LSC is found to scale with $\mathit{Ra}$ as $\mathit{Re}= 0. 13{\mathit{Ra}}^{0. 43\pm 0. 01} $. It is also found that the normalized flow strength $\langle \delta \rangle / \mrm{\Delta} T\times \mathit{Ra}/ \mathit{Pr}\propto {\mathit{Re}}^{1. 5\pm 0. 1} $, with the exponent in good agreement with that predicted by Brown & Ahlers (Phys. Fluids, vol. 20, 2008, p. 075101). A wealth of dynamical features of the LSC, such as the cessations, flow reversals, flow mode transitions, torsional and sloshing oscillations are observed in the high-$\mathit{Pr}$ regime as well.
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Konishi, Tatsuya, Hiroaki Ogawa, Yuho Najima, Shinpei Hashimoto, Atsushi Wada, Hiroto Adachi, Ryosuke Konuma, et al. "Safety of total body irradiation using intensity-modulated radiation therapy by helical tomotherapy in allogeneic hematopoietic stem cell transplantation: a prospective pilot study." Journal of Radiation Research 61, no. 6 (September 5, 2020): 969–76. http://dx.doi.org/10.1093/jrr/rraa078.
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Abstract Total body irradiation using intensity-modulated radiation therapy total body irradiation (IMRT-TBI) by helical tomotherapy in allogeneic hematopoietic stem cell transplantation (allo-HSCT) allows for precise evaluation and adjustment of radiation dosage. We conducted a single-center pilot study to evaluate the safety of IMRT-TBI for allo-HSCT recipients. Patients with hematological malignancies in remission who were scheduled for allo-HSCT with TBI-based myeloablative conditioning were eligible. The primary endpoint was the incidence of adverse events (AEs). Secondary endpoints were engraftment rate, overall survival, relapse rate, non-relapse mortality, and the incidence of acute and chronic graft-versus-host disease (aGVHD and cGVHD, respectively). Between July 2018 and November 2018, ten patients were recruited with a median observation duration of 571 days after allo-HSCT (range, 496–614). D80% for planning target volume (PTV) in all patients was 12.01 Gy. Average D80% values for lungs, kidneys and lenses (right/left) were 7.50, 9.03 and 4.41/4.03 Gy, respectively. Any early AEs (within 100 days of allo-HSCT) were reported in all patients. Eight patients experienced oral mucositis and gastrointestinal symptoms. One patient experienced Bearman criteria grade 3 regimen-related toxicity (kidney and liver). All cases achieved neutrophil engraftment. There was no grade III–IV aGVHD or late AE. One patient died of sinusoidal obstruction syndrome 67 days after allo-HSCT. The remaining nine patients were alive and disease-free at final follow-up. Thus, IMRT-TBI was well tolerated in terms of early AEs in adult patients who underwent allo-HSCT; this warrants further study with longer observation times to monitor late AEs and efficacy.
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Amit, Odelia, Yakir Moshe, Inna Ospovat, Yael Bar-On, Ofrat Beyar-Katz, Dina Tshernichovsy, Irit Avivi, and Ron Ram. "Sequential Therapy with Fitcy Preparative Regimen for Patients with Primary Refractory AML - a Single Center Retrospective Analysis." Blood 138, Supplement 1 (November 5, 2021): 2860. http://dx.doi.org/10.1182/blood-2021-152699.
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Abstract Introduction - primary refractory AML is associated with a dismal prognosis. Only 30% of patients will respond to salvage chemotherapy and continue to allogeneic hematopoietic cell transplantation (HCT) with a 10-20% long- term overall survival. Following from the FLAMSA protocol, we implemented a modified RIC regimen - FITCy (fludarabine, cytarabine +/- idarubicin and 4 Gy TBI) in all primary refractory patients with a donor available for transplant. Methods - all patients who were admitted with AML, were identified by the transplantation coordinator nurse and underwent donor evaluation within 2 days from diagnosis. Patients who received induction chemotherapy had a day 14 marrow examination and where leukaemia blasts were identified, donor search was prioritized. These patients went on to have a day 28 bone marrow examination to confirm refractory disease. Patients who were treated with azacitidine ±venetoclax had a 2-month BM evaluation and donor search was prioritized in case of refractory disease. All consecutive patients, diagnosed with primary refractory AML, underwent HCT with the FITCy regimen in the Tel Aviv Sourasky Medical Center. Patients who underwent sequential therapy for relapsed disease (either chemosensitive or refractory) or a second HCT were excluded from this analysis. The protocol was amended on January 2018 to include ATG for all patients after interim analysis showed a high rate of GVHD. Results - Between January 2014 and June 2021, 48 patients were identified with primary refractory disease and were eligible for the protocol. Median age was 63 (range, 22-75) years (Table). Median follow-up for surviving patients was 33 (range, 1-81) months. Prior to HCT, 12 (25%) patients had ongoing documented infections (either microbiology or clinically). Median days to engraftment of neutrophils (>500/dL) and to complete engraftment of platelets (>20000/dL) were 10 (range, 7-20) days, and 16 (9-35) days, respectively. 7 patients with early progression/non relapse mortality were not evaluated for this outcome. No patient had primary/secondary graft rejection. Severe mucositis was observed in only 7 patients (15%) and was mostly observed in the upper gut. 18 patients (38%) developed microbiology documented infections during the neutropenic period and in 7 (40%) this directly contributed to mortality. Only 2 patients (4%) developed sinusoidal obstruction syndrome. Complete remission was documented on day 30, in all but 1 patient with a median whole marrow donor chimerism of 98% (range, 73-100%).Cumulative incidences of grade 2-4 and 3-4 acute GVHD at day 100 were 55% and 15%, respectively. Cumulative incidences of overall chronic GVHD and moderate-severe chronic GVHD at 1 year after HCT were 64% and 24%, respectively. Cumulative incidences of relapse at 1 year and 2 years post HCT were 24% and 30%, respectively. Non-relapse mortality rates, at 30 days, 100 days and 1 year post HCT were 13%, 20%, and 32%, respectively. Cumulative incidences of 1, 2, and 3 years overall survival were 50%, 42%, and 42%, Figure. Cox regression analysis for overall survival identified increased time from diagnosis (HR-1.03, p=.046), mismatched donor (HR-1.4, p=.05) and the use of ATG (HR=.33, p=.006) to impact survival, while age, sex and comorbidity index were not predictive. Conclusions - Sequential therapy in patients with primary refractory AML provides a remarkable anti- leukemic effect. A timely donor search program is essential for the succession of this approach. Nevertheless, infection control and GVHD prophylaxis is still suboptimal and future protocols should focus on these domains while preserving graft vs. leukemia function. Figure 1 Figure 1. Disclosures Moshe: AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Lectures; Astellas: Membership on an entity's Board of Directors or advisory committees, Other: Lectures; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Lectures. Avivi: Novartis: Speakers Bureau; Kite, a Gilead Company: Speakers Bureau. Ram: Novartis: Honoraria; Gilead: Honoraria. OffLabel Disclosure: Off label Cellcepet for prophylaxis of GVHD
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Nickel, Robert Sheppard, John T. Horan, Allistair Abraham, Muna Qayed, Ann Haight, Naomi Luban, and Jeanne E. Hendrickson. "HLA Class I Alloimmunization and Platelet Transfusion Support in HLA-Identical Bone Marrow Transplant for Sickle Cell Disease: A Sickle Transplant Alliance for Research Study." Blood 132, Supplement 1 (November 29, 2018): 3816. http://dx.doi.org/10.1182/blood-2018-99-114116.
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Abstract Introduction: HLA alloimmunziation has been described in patients, including pediatric patients with sickle cell disease (SCD), who received only leukocyte-reduced red blood cell (RBC) transfusions. While HLA alloimmunization has significant implications in bone marrow transplant (BMT) with an HLA-disparate donor (donor-specific HLA antibodies increase the risk of graft rejection), the clinical significance of this alloimmunization in HLA-identical BMT is unclear. In particular, it is unknown whether HLA class I alloimmunization affects platelet transfusion support during BMT. Platelet transfusions are especially important in BMT for SCD because of the historic high incidence of intracranial bleeding and the subsequent adoption of a relatively high platelet transfusion threshold. Methods: We tested for HLA class I alloimmunization using pre-BMT serum or plasma from 32 pediatric patients with SCD undergoing BMT with an HLA-identical sibling donor. HLA class I alloimmunization was evaluated using the FlowPRA® (panel reactive antibody) screening test which detects IgG antibodies to the majority of HLA class I antigens. Pre-BMT, patients had received leukocyte-reduced RBC transfusions. All patients undergoing BMT received leukocyte-reduced, irradiated, apheresis platelet transfusions to maintain a platelet count greater than 50 x 109/L. The number of platelet transfusions received in the first 45 days post-BMT was compared between those with a positive PRA versus those with a negative PRA using a two-sample t-test. Results: Among the 32 patients studied, the mean age at BMT was 9.4 years (range 1-21 years). Pre-BMT, 40% had received greater than 10 RBC transfusions and 32% of the entire cohort was receiving chronic RBC transfusions. BMT conditioning regimens included: traditional myeloablative busulfan, cyclophosphamide, antithymocyte globulin (BU-CY-ATG) (n=10); dose-reduced BU-CY-ATG + fludarabine (flu) (n=16); reduced intensity conditioning (RIC) alemtuzumab, flu, melphalan +/- thiotepa (n=5); and RIC BU-flu-ATG (n=1). All patients received HLA-identical sibling donor bone marrow, with 3 patients receiving a combined bone marrow and cord blood graft. All patients engrafted with 100% survival at day +45. Six patients developed acute graft-versus-host disease (GVHD): 1 grade I, 3 grade II, 1 grade 3, 1 grade 4. No patient had an intracranial bleed or other serious bleeding. From testing of the pre-BMT sample, 11/32 (34%) of patients had a positive HLA class I antibody screen. HLA class I alloimmunized patients received significantly more platelet transfusions than non-alloimmunized patients: mean 19.2 (SD 13.9) vs. 11.2 (SD 8.0) transfusions, p=0.049 (Figure). On univariate analysis, age, sex, conditioning regimen, and GVHD were each not significantly associated with the number of platelet transfusions (p>0.1). Only two patients developed hepatic sinusoidal obstruction syndrome (one HLA alloimmunized patient, one non-alloimmunized patient). Mean day of platelet engraftment was not significantly different between alloimmunized compared to non-alloimmunized patients: day +34.6 (SD 10.6) vs. day +30.2 (SD 11.3), p=0.28. Among HLA class I alloimmunized patients, the mean positive PRA was 19.7% (range 4-55%); there was no association with this PRA value and the number of platelet transfusions (r2=0.0064, p=0.81). Conclusion: In pediatric HLA-identical sibling BMT for SCD, pre-BMT HLA class I alloimmunization (but not the absolute PRA value) appears to be associated with more platelet transfusions. It is unclear if this increased platelet transfusion requirement is due directly to HLA antibody immune-mediated clearance of transfused platelets or other inherent differences of HLA class I alloimmunized patients. Figure. Figure. Disclosures Qayed: Novartis: Consultancy.
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Iuliano, Francesco, Eleonora Iuliano, Alessia Perricelli, Maria Aquila Santoro, Angelo Pomillo, Maria Luci, Pierosandro Tagliaferri, and Pierfrancesco Tassone. "Low Doses of Eltrombopag Are Safe and Effective in the Prophylaxis of the Chemotherapy-Induced Thrombocytopenia (CIT)." Blood 128, no. 22 (December 2, 2016): 4926. http://dx.doi.org/10.1182/blood.v128.22.4926.4926.
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Abstract Chemotherapy-induced-thrombocytopenia (CIT) can prevent the administration of the optimal dose and schedule of anticancer treatment and limit its benefits in the adjuvant or metastatic setting. Therapeutic approaches will include dose delays or reduction ,platelet transfusion and consideration of platelet-stimulating agents. In a review of chemotherapy-induced thrombocytopenia including >47 000 patients with solid tumors, CRC was associated with the highest prevalence of thrombocytopenia by cancer type, and most patients had received a platinum-based chemotherapy regimen. Experimental data demonstrated that Platinum is one of the heavy metals which may induce immune manifestations in humans and in experimental animals. However, novel mechanisms of oxaliplatin-related thrombocytopenia have been implicated and include an immune-dependent mechanism, as well as portal hypertension related to sinusoidal injury yielding splenic sequestration of platelets. Eltrombopag is an oral, non-peptide thrombopoietin receptor agonist that has been shown efficacy and safety in chronic immune thrombocytopenia (ITP) patients not responding to previous therapy .Moreover,some clinical studies demonstrate a role for thrombopoietin agonists in improving compliance with cytotoxic regimens in cancer patients whose chemotherapy was delayed due to thrombocytopenia,[and they suggest that prophylactic use of eltrombopag or romiplostim might reduce the degree and duration of chemotherapy-induced thrombocytopenia. Here, we report on a series of 22 patients at high risk of CIT because of platinum chemotherapy schedules who received low doses eltrombopag as prophilaxis .The aim of the study was to prevent CIT in patients who cannot be supported by platelet transfusions and for whom the maintenance of dose intensity is crucial for remission or survival Methods A total of 22 consecutive adult patients, female (60 %), median age 47 years (range 28 - 67) were enrolled in the study. The reason of chemotherapy has been ovary cancer in 5 patients, colon cancer in 8 patients, relapsed DLBC lymhoma in 4 patients,, TNBC in 2 patients, pancreatic cancer in 3 pts. All patients received eltrombopag 25 mg by mouth twice a weekly as soon as the platelet count falls below 80000 mmc, and continued on treatment until completion of cycles of chemotherapy. Results The mean platelet count nadir was 60000 mmc; the number of days with platelet count < 80000/µL was 4 days; The maximum value reached was 270,000 mmc. No treatment-related toxicity was observe. 1 out of 22 pts , did not respond to the planned dose and received 50 mg for eight consecutive days before each course of chemotherapy.The principal endpoints of the study : avoid nadir platelet counts < 50,000/µL,platelet transfusions, bleeding events, chemotherapy dose reductions , chemotherapy delays. were achieved in all patients. Conclusion In our opinion low dose eltrombopag prophilaxis can be an effective and safe strategy for preventing the CIT. Disclosures No relevant conflicts of interest to declare.
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Motohashi, Kenji, Shin Fujisawa, Makoto Onizuka, Shinichi Kako, Emiko Sakaida, Katsumichi Shono, Raine Tatara, et al. "Effects of the Order of Administration of Total Body Irradiation and Cyclophosphamide on the Outcome of Allogeneic Hematopoietic Cell Transplantation." Blood 124, no. 21 (December 6, 2014): 3900. http://dx.doi.org/10.1182/blood.v124.21.3900.3900.
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Abstract Background and objectives: Total body irradiation (TBI) combined with cyclophosphamide (CY) is one of the most common myeloablative conditioning regimens used in allogeneic hematopoietic stem-cell transplantation (HSCT) for treating hematological malignancies. However, it remains unclear whether the order of administrating TBI and CY has an effect on the outcome in clinical transplantation. The aim of this study is to clarify the effects of the order of TBI and CY administration on the outcome of allogeneic HSCT. Patients and Methods: We retrospectively investigated the clinical outcome of 504 adult patients with acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), and myelodysplastic syndrome who received allogeneic HSCT with myeloablative conditioning regimens consisting of TBI and CY at the transplant centers participating in the Kanto Study Group on Cell Therapy between January 2001 and August 2012. Patients were divided into two groups based on the order in which TBI and CY were administered. The outcome of HSCT and incidences of acute and chronic GVHD, sinusoidal obstruction syndrome / veno-occlusive disease, and idiopathic pneumonia were compared between the two groups.Patients who underwent HSCT during the first or second remission of acute leukemia or refractory anemia of myelodysplastic syndrome were considered as having standard-risk disease. All other conditions were considered as high-risk disease. Results: A total of 218 patients received CY before TBI (CY-TBI) and 286 received CY after TBI (TBI-CY). AML was more common in the CY-TBI group (62.8%) compared with the TBI-CY group (51.0%), and ALL was less common in the CY-TBI group (25.7%) compared with the TBI-CY group (37.8%; P = 0.013). High-risk disease was more frequent in the CY-TBI group (38.5%) compared with the TBI-CY group (23.4%; P < 0.001). The proportion of unrelated bone marrow (54.6% vs. 43.4%) and cord blood transplantation (22.9% vs. 17.8) were higher among patients in the CY-TBI group than in the TBI-CY group (P = 0.0014). TBI was administered at a dose of 12 Gy in 212 patients (97.2%) in the CY-TBI group and 266 patients (93.0%) in the TBI-CY group (P = 0.013). More patients received TBI administered in six fractions in the CY-TBI group (72.9%) than in the TBI-CY group (53.1%; P < 0.001). Female to female transplantation was lower in the CY-TBI (13.3%) group compared with the TBI-CY group (24.1%; P = 0.023). Age, gender, GVHD prophylaxis, and blood mismatch were not significantly different between the two groups. The order in which TBI and CY was administered did not affect the incidence of grades II–IV acute GVHD (45.3% vs. 49.3% at day 100; P = 0.28) and chronic GVHD (36.0% vs. 43.8% at 2 years; P = 0.10), overall survival (52.4% vs. 53.4% at 5 years; P = 0.44), disease-free survival (50.5% vs. 51.5% at 5 years; P = 0.58), relapse rate (30.2% vs. 31.8% at 5 years; P = 0.96) and non-relapse mortality (19.3% vs. 16.7% at 5 years; P = 0.52) in the two groups (CY-TBI and TBI-CY, respectively) by univariate analysis. Moreover, the cumulative incidences of sinusoidal obstruction syndrome / veno-occlusive disease (4.1% vs. 3.8%; P = 0.81) and idiopathic pneumonia were comparable (3.1% vs. 3.4%; P = 0.87) between the two groups (CY-TBI and TBI-CY, respectively). Conclusions: This study demonstrates that the order of administration of TBI and CY does not have an effect on the outcome of allogeneic HSCT. Further studies are warranted to confirm this result. Disclosures No relevant conflicts of interest to declare.
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Damlaj, Moussab, Hassan B. Alkhateeb, Daniel K. Partain, Jehad Almasri, Mehrdad Hefazi, Shahrukh K. Hashmi, Dennis A. Gastineau, et al. "Fludarabine Busulfan Compared to Fludarabine Melphalan Is Associated with Increased Relapse Risk in Reduced Intensity Conditioning Transplant Despite Pharmacokinetic Dosing." Blood 126, no. 23 (December 3, 2015): 736. http://dx.doi.org/10.1182/blood.v126.23.736.736.
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Abstract Background: Fludarabine plus busulfan (FB) and fludarabine plus melphalan (FM) are two commonly used reduced intensity conditioning (RIC) regimens for allogeneic hematopoietic stem cell transplantation (SCT). A recent analysis showed that both regimens had similar overall survival (OS) but relapse incidence (RI) was significantly higher with FB with a trend towards higher non-relapse mortality (NRM) in FM (Baron et al., Cancer 2015). However, that cohort included patients treated with oral and intravenous busulfan without pharmakokinetic targeting of intravenous which may impact anti-leukemic activity. Aim: Compare transplant related outcomes of FB vs. FM using intravenous (IV) busulfan targeted to the area under the curve (AUC). Methods: After due IRB approval, patients with acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS) receiving RIC-SCT from 2008-2014 were identified. All baseline and laboratory features were retrospectively extracted. Busulfan dose in FB was 0.8 mg/kg IV for 10 doses with therapeutic AUC target of 900-1500 mcmol/L (min). All patients received T-cell replete grafts. Categorical and continuous variables were compared using Pearson's chi-squared and Wilcoxon/Kruskal-Wallis, respectively. Survival estimates were calculated using the Kaplan-Meier method and curves were compared using the log-rank test. Cumulative incidence was computed as competing events using Grey's model. Univariate and multivariate analyses were performed using Cox regression modeling. Results: A. Baseline characteristics and AUC monitoring: 134 pts were identified (47 FB and 87 FM). Median follow up of the entire cohort was 40 months (0-63.3) and at last follow up, 60% and 29% have died or relapsed, respectively. Baseline characteristics stratified according to conditioning regimen are shown in table 1. Younger age (60 yrs FB vs. 61 yrs FM, p = 0.015) and a trend towards a higher CMV R-/D- status (28% FB vs. 14% FM p = 0.064) were the only significant differences identified. All patients in the FB group received intravenous busulfan and 46/47 patients had evaluable AUC data with a range of 732-1354 mcmol/L (min). A total of 19 patients were outside of range, all <900 mcmol/L (min) and required a median dose increase of 28.1% (3.3-50.2%) B. Engraftment and toxicity data: The median time for platelet engraftment was 19 days (0-48) for FB vs. 16 days (14-183) for FM (p = 0.0023) whereas the median time to absolute neutrophil count (ANC) engraftment was 18 days (7-30) for FB and 15 days (11-40) for FM (p = 0.077). Cumulative incidence of grade II-IV, III-IV acute GVHD and chronic GVHD at 2-yr was 57.3%, 11% and 52.8% for FB and 48.6%, 17% and 63.4% for FM (p = 0.73, 0.4 and 0.21, respectively). Two patients in the FM group died of cardiac causes (heart failure and sudden cardiac arrest). No cases of sinusoidal obstructive syndrome were observed in either arm C. Transplant outcomes: A significantly higher 2-yr relapse incidence (RI) was associated with FB vs. FM at 35.6% vs 17.3%, respectively (p = 0.0058). 2-yr progression free survival (PFS) was also significantly lower in the FB vs. FM at 51.2% vs. 65.1%, respectively (p 0.031). However, 2-yr OS and NRM was similar for FB vs. FM (53.1% and 22.9% vs 63.9% and 21.9%, respectively p = 0.26 and 0.89). Necessitating a dose adjustment based on AUC did not increase the risk for relapse or affect NRM. In multivariate analysis, FB was associated with increased RI with hazard ratio (HR) 2.29 (1.07-4.88; p = 0.033). Other factors significantly associated with RI on multivariate analysis were secondary/therapy related disease with HR 2.84 (1.34-6.02; p = 0.0067) and CR1 vs. other with HR 0.39 (0.17-5.32; p = 0.019). The significance of the results remained unchanged after exclusion of MDS patients (data not shown) Conclusion: Despite AUC dose adjustment, FB compared to FM was associated with increased RI with a similar OS and NRM. AUC dose adjustment did not impact transplant outcomes and its routine use in RIC should be further evaluated. Given the wide use of FB as a conditioning regimen, these important observations should be prospectively studied in a randomized fashion. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Al-Kali: Novartis: Research Funding. Wolf:Janssen Scientific Affairs, LLC: Consultancy.
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Chaudhry, Muhammad M., Tokir Mujtaba, Zeyar Thet, and Frank W. DiPillo. "Agressive Lymphoma without Lymphadenopathy." Blood 112, no. 11 (November 16, 2008): 5291. http://dx.doi.org/10.1182/blood.v112.11.5291.5291.
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Abstract Hepatosplenic T cell lymphomas are among a rare breed of aggressive non Hodgkin tumors that usually comprise of immature cytotoxic T cells. They most commonly involve young adults who generally present with constitutional symptoms of fever, weight loss and night sweats. Diagnosis can be challenging in the absence of lymphadenopathy and paucity of bone marrow findings. The discovery of neoplastic cells in peripheral blood is often a finding late in the clinical course. Demonstation of sinusoidal infiltration of T cells on either liver or splenic biopsy is ususally diagnostic. These cells are positive for clonal rearrangement of the γ gene of the T cell receptor which is a hallmark of this disease. Prognosis remains poor and most patients die within two years of diagnosis. We report a case of a patient who presented with unexplained fever and hepatosplenomegaly and after extensive workup was diagnosed with hepatosplenic T cell lymphoma. A 42 year old male with no significant past medical history presented with complains of abdominal pain, fever, malaise and 30lb weight loss over a period of six weeks. Pain was described as intermittent episodes of bilateral flank fullness associated with nausea and vomiting. He had traveled to Mexico 8 weeks earlier and according to him his symptoms began soon after his trip. He denied any headaches, cough, shortness of breath,. No dysuria, and no diarrhea. No smoking alcoholism or illicit drug use was reported. No sick or new sexual contacts. Family history was noncontributory. Vital signs were significant for temperature of 101 F. Physical examination revealed presence of marked hepatosplenomegaly. There was no lympadenopathy as well as no murmurs or rubs. Labs showed pancytopenia with blood counts of 2.7, 9.8 and 101 for WBC, Hb and platelets respectively. Additionally, alkaline phosphatase was elevated while rest of the liver functions was normal. Preliminary diagnosis of infectious versus malignant etiology was made. Peripheral smear did not show any malignant cells. Infectious workup returned negative for HIV, hepatitis, histoplasma, brucella, leptospira, coccidioidomycosis, syphilis, leishmaniasis as well as malaria and dengue fever. A bone marrow biopsy was performed for further evaluation and showed moderately hypercellular bone marrow with erythroid and megakaryocytic hyperplasia but no evidence of malignancy or granulomatous process. Meanwhile patient remained persistently febrile without any growth on blood cultues. An echo was normal with no evidence of endocarditis. Tuberculin test was non reactive. Given the results of the bone marrow biopsy and hepatosplenomegaly without any lymphadenopathy it was thought that a localized infiltrative process of he liver or spleen was likely. Patient thus underwent a liver biopsy disclosing intra sinusoidal collections of atypical CD3, CD7, TIA-1 and CD56 positive lymphocytes also bearing T cell receptor clonal rearrangement consistent with a diagnosis of hepatosplenic T-cell lymphoma which was further classified as gammadelta type.. He was subsequently started on ECHOP regimen and is currently in remission on a three month followup Hepatosplenic lymphoma, though is a rare tumor, should be considered in patients with unexplained hepatosplenomegaly without lymphadenopathy and normal peripheral smear. Liver biopsy is diagnostic most of the time.
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Butta, Nora, Carmen de Ramón, Raul Justo Sanz, Elena Monzon Manzano, Ihosvany Fernandez Bello, Mercedes Gasior, Raquel De Paz, et al. "Evaluation of Endothelial Damage in Sinusoidal Obstructive Syndrome." Blood 128, no. 22 (December 2, 2016): 5802. http://dx.doi.org/10.1182/blood.v128.22.5802.5802.
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Abstract Introduction: Sinusoidal Obstructive Syndrome (SOS) is a complication derived from the endothelial damage associated to hematopoietic stem-cell transplant (HSCT) conditioning. Although its appearance is highly dependent on patient risk factors, it has an estimated prevalence of 14% and is associated with a high morbidity and with mortality rates than can ascend to 90% at day +100 of transplant in severe cases. New methods to early diagnose SOS are needed in order to minimize the incidence and severity of SOS. Here we present preliminary results of our single center prospective study that aims to measure and validate a panel of biomarkers in plasma [L-Ficolin, hyaluronic acid (HA), vascular adhesion molecule-1 (VCAM1) and plasminogen activator inhibitor-1 (PAI-1)] which have been recently described to be prognostic of the development of SOS (Akil et al, Biol. Blood Marrow Transplant. 21, 1739-1745, 2015). Methods: Twenty-one adult patients undergoing HSCT were recruited (median age 43.5 years old, 20-68), 15 men and 6 women. Three patients (14%) were diagnosed of SOS and received defibrotide (Gentium/Jazz Pharmaceutical) treatment. Diagnosis of SOS was performed based on the Seattle and Baltimore modified Criteria. Citrated blood samples from all patients were obtained before starting conditioning regimen (V0), and at infusion day (V1), 7 (V2) and 14 (V3) after infusion. Three additional samples (V4, V5 and V6) were drawn from those patients with SOS (just before defibrotide and 7 and 14 days after treatment with defibrotide). Samples were centrifuged twice at 23°C (15 min at 1,500 g, and 2 min at 13,000 g) and aliquots were stored at -80ºC until analysis. Phosphatidylserine-MP (Ph-MP) and tissue factor-MP (TF-MP) dependent procoagulant activities were determined with the ZYMUPHEN kits. VCAM1, PAI-1, L-Ficolin and HA concentrations were measured by ELISA. Data from the routine laboratory analysis were also registered. Statistical analyses was performed with SPSS software. Values of p≤0.05 were considered statistically significant. Results : Considering transplant type, 9 were autologous and 9 allogenic in controls, and 3 allogenic in SOS; donor type were 3 unrelated, 6 related and 3 haploidentical in controls, and 3 related and 2 haploidentical in SOS. Conditioning regimen intensity was 7 full, 2 reduced, 8 with busulfan and 1 with total body irradiation in controls and 3 reduced and 2 with busulfan in SOS group. Controls received 2(1-4) previous chemotherapy lines whereas SOS group received 3(2-9). Regarding diseases, 4 presented acute myeloblastic leukemia, 2 acute lymphoblastic leukemia, 3 multiple myeloma, 3 non-Hodgkin's lymphoma and 6 Hodgkin's disease in control group whereas in SOS group 1 had acute myeloblastic leukemia, 1 myelodysplastic syndrome and 1 non-Hodgkin's lymphoma. As observed, occurrence of SOS did not seem to be related to either the malignant disease or number of chemotherapy drugs employed for its treatment or donor type and conditioning regimen. L-Ficolin, a complement activator involved in homeostatic clearance of mitochondria in the liver, seemed to diminished in the SOS group at V3 (wo SOS : 1025±923 ng/mL ; SOS : 680±817 ng/mL). Nevertheless, this diminution was not significant probably due to the few patients with SOS. No differences were observed between patients without and with SOS in plasma levels of markers of endothelial damage VCAM1, PAI-1 and HA, this last a direct indicator of hepatic sinusoidal endothelial cell function. Procoagulant activity associated to Ph-MP was lower in patients with SOS (p=0.023) whereas that associated to TF-MP was unaffected. Plasma levels of VCAM1 and HA increased along time in both groups. After treatment with defibrotide these values achieved steady levels in SOS patients (V4 and V5). On the other hand, PAI-1 did not change over time. SOS patients presented at V3 higher total bilirrubin (wo SOS: 0.86±0.53 mg/dL; SOS: 2.31±0.18 mg/dL, p=0.008) and lower albumin levels (wo SOS: 3.5±0.3 g/dL; SOS: 2.7±0.1 g/dL) Conclusions: Our results indicate that endothelial damage is present in all patients undergoing HSCT and that treatment of SOS patients with defibrotide might restrain this injury. Due to the low number of patients included so far, we cannot conclude anything about the value of biomarkers proposed to serve as predictors of SOS onset. Our study is still open and recruiting patients. This work was supported by Jazz Pharmaceutical Disclosures No relevant conflicts of interest to declare.