Back to the Future! The Evolving Role of Maintenance Therapy after Hematopoietic Stem Cell Transplantation

AbstractRelapse is a devastating event for patients with hematologic cancers treated with hematopoietic stem cell transplantation. In most situations, relapse treatment options are limited. Maintenance therapy offers the possibility of delaying or avoiding disease recurrence, but its role remains unclear in most conditions that we treat with transplantation. Here, Dr. Hourigan presents an overview of minimal residual disease (MRD) measurement in hematologic malignancies and the applicability of MRD-based post-transplantation interventions. Dr. McCarthy reviews current knowledge of maintenance therapy in the autologous transplantation context, with emphasis on immunologic interventions and immune modulation strategies designed to prevent relapse. Dr. de Lima discusses current lines of investigation in disease recurrence prevention after allogeneic transplantation, focusing on acute myeloid leukemia and myelodysplastic syndrome

Simulation of the Control of Vortex Breakdown in a Closed Cylinder Using a Small Rotating Disk

The enhancement or suppression of vortex breakdown in a closed cylinder caused by a small rotating disk embedded in the nonrotating endwall is simulated in this study. This paper shows that corotation or counter-rotation of the control disk with respect to the driving lid is able to promote or suppress the “bubble-type” vortex breakdown. This is achieved using only a small fraction of the power required to drive the main lid. The simulations show that the vortex breakdown induced or suppressed by flow control displays similar characteristics near the breakdown region as produced by varying the flow Reynolds number. These include near-axis swirl, centerline axial velocity, and centerline pressure. The influence of the size of the control disk is also quantified

The present and future of measurable residual disease testing in acute myeloid leukemia

Considerable progress has been made in the past several years in the scientific understanding of, and available treatments for, acute myeloid leukemia (AML). Achievement of a conventional remission, evaluated cytomorphologically via small bone marrow samples, is a necessary but not sufficient step toward cure. It is increasingly appreciated that molecular or immunophenotypic methods to identify and quantify measurable residual disease (MRD) – populations of leukemia cells below the cytomorphological detection limit – provide refined information on the quality of response to treatment and prediction of the risk of AML recurrence and leukemia-related deaths. The principles and practices surrounding MRD remain incompletely determined however and the genetic and immunophenotypic heterogeneity of AML may prevent a one-sizefits- all approach. Here, we review the current approaches to MRD testing in AML, discuss strengths and limitations, highlight recent technological advances that may improve such testing, and summarize ongoing initiatives to generate the clinical evidence needed to advance the use of MRD testing in patients with AML

Three-dimensional Calculations of High and Low-mass Planets Embedded in Protoplanetary Discs

We analyse the non-linear, three-dimensional response of a gaseous, viscous protoplanetary disc to the presence of a planet of mass ranging from one Earth mass (1 M$_e$) to one Jupiter mass (1 M$_J$) by using the ZEUS hydrodynamics code. We determine the gas flow pattern, and the accretion and migration rates of the planet. The planet is assumed to be in a fixed circular orbit about the central star. It is also assumed to be able to accrete gas without expansion on the scale of its Roche radius. Only planets with masses M \gsim 0.1 M$_J$ produce significant perturbations in the disc's surface density. The flow within the Roche lobe of the planet is fully three-dimensional. Gas streams generally enter the Roche lobe close to the disc midplane, but produce much weaker shocks than the streams in two-dimensional models. The streams supply material to a circumplanetary disc that rotates in the same sense as the planet's orbit. Much of the mass supply to the circumplanetary disc comes from non-coplanar flow. The accretion rate peaks with a planet mass of approximately 0.1 M$_J$ and is highly efficient, occurring at the local viscous rate. The migration timescales for planets of mass less than 0.1 M$_J$, based on torques from disc material outside the planets' Roche lobes, are in excellent agreement with the linear theory of Type I (non-gap) migration for three-dimensional discs. The transition from Type I to Type II (gap) migration is smooth, with changes in migration times of about a factor of 2. Starting with a core which can undergo runaway growth, a planet can gain up to a few M$_J$ with little migration. Planets with final masses of order 10 M$_J$ would undergo large migration, which makes formation and survival difficult.Comment: Accepted by MNRAS, 18 pages, 13 figures (6 degraded resolution). Paper with high-resolution figures available at http://www.astro.ex.ac.uk/people/mbate

The effect of MHD turbulence on massive protoplanetary disk fragmentation

Massive disk fragmentation has been suggested to be one of the mechanisms leading to the formation of giant planets. While it has been heavily studied in quiescent hydrodynamic disks, the effect of MHD turbulence arising from the magnetorotational instability (MRI) has never been investigated. This paper fills this gap and presents 3D numerical simulations of the evolution of locally isothermal, massive and magnetized disks. In the absence of magnetic fields, a laminar disk fragments and clumps are formed due to the effect of self--gravity. Although they disapear in less than a dynamical timescale in the simulations because of the limited numerical resolution, various diagnostics suggest that they should survive and form giant planets in real disks. When the disk is magnetized, it becomes turbulent at the same time as gravitational instabilities develop. At intermediate resolution, no fragmentation is observed in these turbulent models, while a large number of fragments appear in the equivalent hydrodynamical runs. This is because MHD turbulence reduces the strength of the gravitational instability. As the resolution is increased, the most unstable wavelengths of the MRI are better resolved and small scale angular momentum transport starts to play a role: fragments are found to form in massive and turbulent disks in that case. All of these results indicate that there is a complicated interaction between gravitational instabilities and MHD turbulence that influences disk fragmentation processes.Comment: 8 pages, 8 figures, accepted for publication in Astronomy & Astrophysic

Pre-emptive detection and evolution of relapse in acute myeloid leukemia by flow cytometric measurable residual disease surveillance

Measurable residual disease (MRD) surveillance in acute myeloid leukemia (AML) may identify patients destined for relapse and thus provide the option of pre-emptive therapy to improve their outcome. Whilst flow cytometric MRD (Flow-MRD) can be applied to high-risk AML/ myelodysplasia patients, its diagnostic performance for detecting impending relapse is unknown. We evaluated this in a cohort comprising 136 true positives (bone marrows preceding relapse by a median of 2.45 months) and 155 true negatives (bone marrows during sustained remission). At an optimal Flow-MRD threshold of 0.040%, clinical sensitivity and specificity for relapse was 74% and 87% respectively (51% and 98% for Flow-MRD ≥ 0.1%) by ‘different-from-normal’ analysis. Median relapse kinetics were 0.78 log10/month but significantly higher at 0.92 log10/month for FLT3-mutated AML. Computational (unsupervised) Flow-MRD (C-Flow-MRD) generated optimal MRD thresholds of 0.036% and 0.082% with equivalent clinical sensitivity to standard analysis. C-Flow-MRD-identified aberrancies in HLADRlow or CD34+CD38low (LSC-type) subpopulations contributed the greatest clinical accuracy (56% sensitivity, 90% specificity) and notably, by longitudinal profiling expanded rapidly within blasts in &gt; 40% of 86 paired MRD and relapse samples. In conclusion, flow MRD surveillance can detect MRD relapse in high risk AML and its evaluation may be enhanced by computational analysis.<br/

Have proto-planetary discs formed planets?

It has recently been noted that many discs around T Tauri stars appear to comprise only a few Jupiter-masses of gas and dust. Using millimetre surveys of discs within six local star-formation regions, we confirm this result, and find that only a few percent of young stars have enough circumstellar material to build gas giant planets, in standard core accretion models. Since the frequency of observed exo-planets is greater than this, there is a `missing mass' problem. As alternatives to simply adjusting the conversion of dust-flux to disc mass, we investigate three other classes of solution. Migration of planets could hypothetically sweep up the disc mass reservoir more efficiently, but trends in multi-planet systems do not support such a model, and theoretical models suggest that the gas accretion timescale is too short for migration to sweep the disc. Enhanced inner-disc mass reservoirs are possible, agreeing with predictions of disc evolution through self-gravity, but not adding to millimetre dust-flux as the inner disc is optically thick. Finally, the incidence of massive discs is shown to be higher at the {\it proto}stellar stages, Classes 0 and I, where discs substantial enough to form planets via core accretion are abundant enough to match the frequency of exo-planets. Gravitational instability may also operate in the Class 0 epoch, where half the objects have potentially unstable discs of \ga30 % of the stellar mass. However, recent calculations indicate that forming gas giants inside 50 AU by instability is unlikely, even in such massive discs. Overall, the results presented suggest that the canonically 'proto-planetary' discs of Class II T Tauri stars {\bf have globally low masses in dust observable at millimetre wavelengths, and conversion to larger bodies (anywhere from small rocks up to planetary cores) must already have occurred.}Comment: Accepted for publication in MNRAS (main journal

Repair of Impaired Pulmonary Function Is Possible in Very-Long-Term Allogeneic Stem Cell Transplantation Survivors

AbstractBoth early- and late-onset noninfectious pulmonary injury are important contributors to the nonrelapse mortality seen after allogeneic stem cell transplantation (allo-SCT), particularly in subjects conditioned with high-dose total body irradiation (TBI). To characterize the kinetics of recovery from pulmonary injury in long-term survivors, we collected data on 138 subjects who survived > 3 years (median survival, 10.2 years) after predominantly TBI-based allo-SCT from their HLA-matched siblings. Baseline pulmonary function tests served as the reference for subsequent measurements at 3, 5, 10, and 15 years for each survivor. The only parameter showing a clinically and statistically significant decline post-transplant was adjusted diffusion capacity of lung for carbon monoxide (DLCO), which reached a nadir at 5 years but surprisingly normalized at the 10-year mark. Multivariable modeling identified chronic graft-versus-host disease (P < .02) and abnormal baseline-adjusted DLCO (P < .03) as the only significant factors associated with the decline in adjusted DLCO at 5 years but excluded smoking, conditioning intensity, baseline C-reactive protein level, TBI dose to the lungs, disease, and demographic variables. In conclusion, pulmonary injury as monitored by the adjusted DLCO continues to deteriorate in the first 5 years after allo-SCT but recovers at 10 years

A review of the surgical conversion rate and independent management of spinal extended scope practitioners in a secondary care setting

INTRODUCTION Spinal orthopaedic triage aims to reduce unnecessary referrals to surgical consultants, thereby reducing waiting times to be seen by a surgeon and to surgical intervention. This paper presents an evaluation of a spinal orthopaedic triage service in the third largest spinal unit in the UK. METHODS A retrospective service evaluation spanning 2012 to 2014 was undertaken by members of the extended scope practitioner (ESP) team to evaluate the ESPs’ ability to manage patient care independently and triage surgical referrals appropriately. Data collected included rates of independent management, referral rates for surgical consideration and conversion to surgery. Patient satisfaction rates were evaluated retrospectively from questionnaires given to 5% of discharged patients. RESULTS A total of 2,651 patients were seen. The vast majority (92%) of all referrals seen by ESPs were managed independently. Only 8% required either a discussion with a surgeon to confirm management or for surgical review. Of the latter, 81% were considered to be suitable surgical referrals. A 99% satisfaction rate was reported by discharged patients. CONCLUSIONS ESP services in a specialist spinal service are effective in managing spinal conditions conservatively and identifying surgical candidates appropriately. Further research is needed to confirm ESPs’ diagnostic accuracy, patient outcomes and cost effectiveness