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

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

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

Minimal residual disease prior to allogeneic hematopoietic cell transplantation in acute myeloid leukemia: a meta-analysis

Minimal residual disease prior to allogeneic hematopoietic cell transplantation has been associated with increased risk of relapse and death in patients with acute myeloid leukemia, but detection methodologies and results vary widely. We performed a systematic review and meta-analysis evaluating the prognostic role of minimal residual disease detected by polymerase chain reaction or multiparametric flow cytometry before transplant. We identified 19 articles published between January 2005 and June 2016 and extracted hazard ratios for leukemia-free survival, overall survival, and cumulative incidences of relapse and non-relapse mortality. Pre-transplant minimal residual disease was associated with worse leukemia-free survival (HR=2.76 [1.90-4.00]), overall survival (HR=2.36 [1.73-3.22]), and cumulative incidence of relapse (HR=3.65 [2.53-5.27]), but not non-relapse mortality (HR=1.12 [0.81-1.55]). These associations held regardless of detection method, conditioning intensity, and patient age. Adverse cytogenetics was not an independent risk factor for death or relapse. There was more heterogeneity among studies using flow cytometry-based than WT1 polymerase chain reaction-based detection (I(2)=75.1% vs. <0.1% for leukemia-free survival, 67.8% vs. <0.1% for overall survival, and 22.1% vs. <0.1% for cumulative incidence of relapse). These results demonstrate a strong relationship between pre-transplant minimal residual disease and post-transplant relapse and survival. Outcome heterogeneity among studies using flow-based methods may underscore site-specific methodological differences or differences in test performance and interpretation

Allogeneic Hematopoietic Cell Transplantation Improves Outcome in Myelodysplastic Syndrome Across High-Risk Genetic Subgroups:Genetic Analysis of the Blood and Marrow Transplant Clinical Trials Network 1102 Study

PURPOSE:Allogeneic hematopoietic cell transplantation (HCT) in patients with myelodysplastic syndrome (MDS) improves overall survival (OS). We evaluated the impact of MDS genetics on the benefit of HCT in a biological assignment (donor v no donor) study.METHODS:We performed targeted sequencing in 309 patients age 50-75 years with International Prognostic Scoring System (IPSS) intermediate-2 or high-risk MDS, enrolled in the Blood and Marrow Transplant Clinical Trials Network 1102 study and assessed the association of gene mutations with OS. Patients with TP53 mutations were classified as TP53multihit if two alleles were altered (via point mutation, deletion, or copy-neutral loss of heterozygosity).RESULTS:The distribution of gene mutations was similar in the donor and no donor arms, with TP53 (28% v 29%; P =.89), ASXL1 (23% v 29%; P =.37), and SRSF2 (16% v 16%; P =.99) being most common. OS in patients with a TP53 mutation was worse compared with patients without TP53 mutation (21% ± 5% [SE] v 52% ± 4% at 3 years; P &lt;.001). Among those with a TP53 mutation, OS was similar between TP53single versus TP53multihit (22% ± 8% v 20% ± 6% at 3 years; P =.31). Considering HCT as a time-dependent covariate, patients with a TP53 mutation who underwent HCT had improved OS compared with non-HCT treatment (OS at 3 years: 23% ± 7% v 11% ± 7%; P =.04), associated with a hazard ratio of 3.89; 95% CI, 1.87 to 8.12; P &lt;.001 after adjustment for covariates. OS among patients with molecular IPSS (IPSS-M) very high risk without a TP53 mutation was significantly improved if they had a donor (68% ± 10% v 0% ± 12% at 3 years; P =.001).CONCLUSION:HCT improved OS compared with non-HCT treatment in patients with TP53 mutations irrespective of TP53 allelic status. Patients with IPSS-M very high risk without a TP53 mutation had favorable outcomes when a donor was available.</p