What Is the Role of HSCT in Philadelphia-Chromosome-Positive and Philadelphia-Chromosome-Like ALL in the Tyrosine Kinase Inhibitor Era?

Previously, the outcome of paediatric Philadelphia-chromosome-positive (Ph+) ALL treated with conventional chemotherapy alone was poor, necessitating the use of haematopoietic stem cell transplantation (HSCT) for the best outcomes. The recent addition of tyrosine kinase inhibitors (TKIs) alongside the chemotherapy regimens for Ph+ ALL has markedly improved outcomes, replacing the need for HSCT for lower risk patients. An additional poor prognosis group of Philadelphia-chromosome-like (Ph-like) ALL has also been identified. This group also can be targeted by TKIs in combination with chemotherapy, but the role of HSCT in this population is not clear. The impact of novel targeted immunotherapies (chimeric antigen receptor T cells and bispecific or drug-conjugated antibodies) has improved the outcome of patients, in combination with chemotherapy, and made the role of HSCT as the optimal curative therapy for Ph+ ALL and Ph-like ALL less clear. The prognosis of patients with Ph+ ALL and persistent minimal residual disease (MRD) at the end of consolidation despite TKI therapy or with additional genetic risk factors remains inferior when HSCT is not used. For such high-risk patients, HSCT using total-body-irradiation-containing conditioning is currently recommended. This review aims to provide an update on the current and future role of HSCT for Ph+ ALL and addresses key questions related to the management of these patients, including the role of HSCT in first complete remission, MRD evaluation and related actions post HSCT, TKI usage post HSCT, and the putative role of HSCT in Ph-like ALL.Peer reviewe

Climate Action In Megacities 3.0

"Climate Action in Megacities 3.0" (CAM 3.0) presents major new insights into the current status, latest trends and future potential for climate action at the city level. Documenting the volume of action being taken by cities, CAM 3.0 marks a new chapter in the C40-Arup research partnership, supported by the City Leadership Initiative at University College London. It provides compelling evidence about cities' commitment to tackling climate change and their critical role in the fight to achieve global emissions reductions

Is it possible to separate the graft-versus-leukemia (GVL) effect against B cell acute lymphoblastic leukemia from graft-versus-host disease (GVHD) after hematopoietic cell transplant?

Hematopoietic cell transplant is a curative therapy for many pediatric patients with high risk acute lymphoblastic leukemia. Its therapeutic mechanism is primarily based on the generation of an alloreactive graft-versus-leukemia effect that can eliminate residual leukemia cells thus preventing relapse. However its efficacy is diminished by the concurrent emergence of harmful graft-versus-host disease disease which affects healthly tissue leading to significant morbidity and mortality. The purpose of this review is to describe the interventions that have been trialed in order to augment the beneficial graft-versus leukemia effect post-hematopoietic cell transplant while limiting the harmful consequences of graft-versus-host disease. This includes many emerging and promising strategies such a

Near Real-Time Use of Optical Remote Sensing and Synthetic Aperture Radar for Response to Central U.S. Flooding in Late April-Early May 2017

No abstract availabl

Climatology, storm morphologies, and environments of tornadoes in the British Isles: 1980–2012

A climatology is developed for tornadoes during 1980–2012 in the British Isles, defined in this article as England, Scotland, Wales, Northern Ireland, Republic of Ireland, Channel Islands, and the Isle of Man. The climatology includes parent storm type, interannual variability, annual and diurnal cycles, intensities, oc- currence of outbreaks (defined as three or more tornadoes in the same day), geographic distribution, and environmental conditions derived from proximity soundings of tornadoes. Tornado reports are from the Tornado and Storm Research Organization (TORRO). Over the 33 years, there were a mean of 34.3 tor- nadoes and 19.5 tornado days (number of days in which at least one tornado occurred) annually. Tornadoes and tornado outbreaks were most commonly produced from linear storms, defined as radar signatures at least 75 km long and approximately 3 times as long as wide. Most (78%) tornadoes occurred in England. The probability of a tornado within 10 km of a point was highest in the south, southeast, and west of England. On average, there were 2.5 tornado outbreaks every year. Where intensity was known, 95% of tornadoes were classified as F0 or F1 with the remainder classified as F2. There were no tornadoes rated F3 or greater during this time period. Tornadoes occurred throughout the year with a maximum from May through October. Finally, tornadoes tended to occur in low-CAPE, high-shear environments. Tornadoes in the British Isles were difficult to predict using only sounding-derived parameters because there were no clear thresholds between null, tornadic, outbreak, and significant tornado cases

National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Immune Dysregulation and Pathobiology Working Group Report

Immune reconstitution after hematopoietic stem cell transplantation (HCT) beyond 1 year is not completely understood. Many transplant recipients who are free of graft-versus-host disease (GVHD) and not receiving any immunosuppression more than 1 year after transplantation seem to be able to mount appropriate immune responses to common pathogens and respond adequately to immunizations. However, 2 large registry studies over the last 2 decades seem to indicate that infection is a significant cause of late mortality in some patients, even in the absence of concomitant GVHD. Research on this topic is particularly challenging for several reasons. First, there are not enough long-term follow-up clinics able to measure even basic immune parameters late after HCT. Second, the correlation between laboratory measurements of immune function and infections is not well known. Third, accurate documentation of infectious episodes is notoriously difficult. Finally, it is unclear what measures can be implemented to improve the immune response in a clinically relevant way. A combination of long-term multicenter prospective studies that collect detailed infectious data and store samples as well as a national or multinational registry of clinically significant infections (eg, vaccine-preventable severe infections, opportunistic infections) could begin to address our knowledge gaps. Obtaining samples for laboratory evaluation of the immune system should be both calendar and eventdriven. Attention to detail and standardization of practices regarding prophylaxis, diagnosis, and definitions of infections would be of paramount importance to obtain clean reliable data. Laboratory studies should specifically address the neogenesis, maturation, and exhaustion of the adaptive immune system and, in particular, how these are influenced by persistent alloreactivity, inflammation, and viral infection. Ideally, some of these long-term prospective studies would collect information on long-term changes in the gut microbiome and their influence on immunity. Regarding enhancement of immune function, prospective measurement of the response to vaccines late after HCT in a variety of clinical settings should be undertaken to better understand the benefits as well as the limitations of immunizations. The role of intravenous immunoglobulin is still not well defined, and studies to address it should be encouraged

The Physiological Mechanisms of Effect of Vitamins and Amino Acids on Tendon and Muscle Healing: A Systematic Review

© 2018 Human Kinetics, Inc.To evaluate the current literature via systematic review to ascertain whether amino acids/vitamins provide any influence on musculotendinous healing and if so, by which physiological mechanisms. Methods: EBSCO, PubMed, ScienceDirect, Embase Classic/Embase, and MEDLINE were searched using terms including "vitamins," "amino acids," "healing," "muscle," and "tendon." The primary search had 479 citations, of which 466 were excluded predominantly due to nonrandomized design. Randomized human and animal studies investigating all supplement types/forms of administration were included. Critical appraisal of internal validity was assessed using the Cochrane risk of Bias Tool or the Systematic Review Centre for Laboratory Animal Experimentation Risk of Bias Tool for human and animal studies, respectively. Two reviewers performed duel data extraction. Results: Twelve studies met criteria for inclusion: eight examined tendon healing and four examined muscle healing. All studies used animal models, except two human trials using a combined integrator. Narrative synthesis was performed via content analysis of demonstrated statistically significant effects and thematic analysis of proposed physiological mechanisms of intervention. Vitamin C/taurine demonstrated indirect effects on tendon healing through antioxidant activity. Vitamin A/glycine showed direct effects on extracellular matrix tissue synthesis. Vitamin E shows an antiproliferative influence on collagen deposition. Leucine directly influences signaling pathways to promote muscle protein synthesis. Discussion: Preliminary evidence exists, demonstrating that vitamins and amino acids may facilitate multilevel changes in musculotendinous healing; however, recommendations on clinical utility should be made with caution. All animal studies and one human study showed high risk of bias with moderate interobserver agreement (k = 0.46). Currently, there is limited evidence to support the use of vitamins and amino acids for musculotendinous injury. Both high-quality animal experimentation of the proposed mechanisms confirming the physiological influence of supplementation and human studies evaluating effects on tissue morphology and biochemistry are required before practical application.Peer reviewe

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-Versus-Host Disease: III. The 2014 Biomarker Working Group Report

Biology-based markers to confirm or aid in the diagnosis or prognosis of chronic GVHD after allogeneic hematopoietic cell transplantation (HCT) or monitor its progression are critically needed to facilitate evaluation of new therapies. Biomarkers have been defined as any characteristic that is objectively measured and evaluated as an indicator of a normal biological or pathogenic process, a pharmacologic response to a therapeutic intervention. Applications of biomarkers in chronic GVHD clinical trials or patient management include: a) diagnosis and assessment of chronic GVHD disease activity, including distinguishing irreversible damage from continued disease activity, b) prognostic risk to develop chronic GVHD, and c) prediction of response to therapy. Sample collection for chronic GVHD biomarkers studies should be well-documented following established quality control guidelines for sample acquisition, processing, preservation and testing, at intervals that are both calendar- and event-driven. The consistent therapeutic treatment of subjects and standardized documentation needed to support biomarker studies are most likely to be provided in prospective clinical trials. To date, no chronic GVHD biomarkers have been qualified for utilization in clinical applications. Since our previous chronic GVHD Biomarkers Working Group report in 2005, an increasing number of chronic GVHD candidate biomarkers are available for further investigation. This paper provides a four-part framework for biomarker investigations: identification, verification, qualification, and application with terminology based on Food and Drug Administration and European Medicines Agency guidelines

Circulating Angiogenic Factors Associated with Response and Survival in Patients with Acute Graft-versus-Host Disease: Results from Blood and Marrow Transplant Clinical Trials Network 0302 and 0802

AbstractCirculating angiogenic factors (AF) reflect tissue healing capacity, although some AF can also contribute to inflammation and are indicative of endothelial dysfunction. The AF milieu in acute graft-versus-host disease (aGVHD) has not been broadly characterized. We hypothesized that patients with abundant AF involved in repair/regeneration versus those mediating damage/inflammation would have improved outcomes. Circulating AF known predominantly for repair/regeneration (epidermal growth factor [EGF], fibroblast growth factor-1 and -2, heparin binding–EGF–like growth factor, and vascular endothelial growth factor-A [VEGF-A], -C, and -D) and for damage/inflammation (angiopoietin-2, endothelin-1, soluble endoglin [sEng], follistatin [FS], leptin, and placental growth factor [PlGF]) were measured in a discovery set of hematopoietic cell recipients with grade III and IV aGVHD and compared with controls, then validated in 2 aGVHD cohorts enrolled in Blood and Marrow Transplant Clinical Trials Network (BMT CTN) trials 0302 (n = 105, serum) and 0802 (n = 158, plasma) versus controls without aGVHD (n = 53, serum). Levels of EGF and VEGF-A were lower than in controls at the onset of aGVHD in both trials and higher with complete response to first-line aGVHD therapy in CTN 0802. FS and PlGF were elevated in aGVHD measured in either serum or plasma. At day 28 after initial aGVHD therapy, elevated FS was an independent negative prognostic factor for survival in both cohorts (hazard ratio, 9.3 in CTN 0302; 2.8 in CTN 0802). These data suggest that circulating AF are associated with clinical outcomes after aGVHD and, thus, may contribute to both pathogenesis and recovery