bluuebunny/crossref_metadata_2025_split huggingface dataset:
HLA donor-specific antibodies in allogeneic hematopoietic stem cell transplantation: challenges and opportunities
Authors: Gladstone Douglas E. , Bettinotti Maria P. 
Published: April 2019

Abstract
Allogenic hematopoietic stem cell recipients may have preformed antibodies directed against foreign HLA antigens. The use of partially HLA-mismatched allogeneic hematopoietic stem cell donors allows for the possibility of the presence of circulating HLA donor-specific antibodies (DSAs) in the recipient. The presence of DSAs at the time of stem cell infusion increases the risk of primary graft failure. More recently developed technology using solid phase immunoassays (SPIs) with fluorochrome-conjugated beads has greatly improved the ability to detect and classify DSAs. When used in combination with the classic lymphocytotoxic complement-dependent and flow cytometric crossmatch tests, SPIs help provide DSA strength assessment. Parous females frequently harbor DSAs. DSAs tend to be of higher intensity when directed against haploidentical first-degree relatives. DSA assessment requires frequent monitoring as their relative strength can change over time. Although the criteria that constitutes a prohibitive DSA is unknown, desensitization techniques can result in engraftment rates as experienced in fully HLA-matched allogeneic blood or marrow transplantation recipients.
Clinical implications of somatic mutations in aplastic anemia and myelodysplastic syndrome in genomic age
Authors: Maciejewski Jaroslaw P. , Balasubramanian Suresh K. 
Published: April 2019

AbstractRecent technological advances in genomics have led to the discovery of new somatic mutations and have brought deeper insights into clonal diversity. This discovery has changed not only the understanding of disease mechanisms but also the diagnostics and clinical management of bone marrow failure. The clinical applications of genomics include enhancement of current prognostic schemas, prediction of sensitivity or refractoriness to treatments, and conceptualization and selective application of targeted therapies. However, beyond these traditional clinical aspects, complex hierarchical clonal architecture has been uncovered and linked to the current concepts of leukemogenesis and stem cell biology. Detection of clonal mutations, otherwise typical of myelodysplastic syndrome, in the course of aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria has led to new pathogenic concepts in these conditions and created a new link between AA and its clonal complications, such as post-AA and paroxysmal nocturnal hemoglobinuria. Distinctions among founder vs subclonal mutations, types of clonal evolution (linear or branching), and biological features of individual mutations (sweeping, persistent, or vanishing) will allow for better predictions of the biologic impact they impart in individual cases. As clonal markers, mutations can be used for monitoring clonal dynamics of the stem cell compartment during physiologic aging, disease processes, and leukemic evolution.
HITs and misses in 100 years of heparin
Authors: Rice Lawrence 
Published: April 2019

Abstract
Heparin was discovered 100 years ago, and the heparin-induced thrombocytopenia syndrome was described 40 years ago. That the most powerful anticoagulant of the last century can also produce the most extreme prothrombotic diathesis is but one of the paradoxes that surround heparin-induced thrombocytopenia. Standard treatment is alternative anticoagulation. Advances continue to be made regarding pathophysiology, prevention, and treatment. Currently, an epidemic of overdiagnosis threatens the well-being of patients, so efforts to educate clinicians on when and how to make this diagnosis are pressing.
Thrombectomy and thrombolysis for the prevention and treatment of postthrombotic syndrome
Authors: Vedantham Suresh 
Published: April 2019

Abstract
Postthrombotic syndrome (PTS) is a frequent complication of lower-extremity deep vein thrombosis (DVT), occurring in approximately 40% of patients despite the use of anticoagulant therapy. PTS causes significant impairment of patients’ health-related quality of life, and no evidence-based therapies have been consistently effective. Catheter-directed thrombolysis and thrombectomy have been shown to remove acute thrombus, and it has been hypothesized they could prevent or reduce PTS. However, because these procedures can be associated with complications, mainly bleeding, randomized trial data are needed to determine when they should be used. In this article, I summarize the current status of thrombus removal procedures for DVT to provide contemporary guidance to clinicians seeking to individualize treatment decisions for their patients.
Inferior vena cava filter use and patient safety: legacy or science?
Authors: Geerts William , Selby Rita 
Published: April 2019

Abstract
There has been a dramatic increase in vena cava filter (VCF) use over the past 20 years in the absence of evidence that filters provide a net patient benefit or are required in most cases. This increase is largely attributable to the availability of retrievable filters and expanded indications, particularly as primary prophylaxis in patients thought to be at high risk of pulmonary embolism. Substantial variability in VCF use, unrelated to patient clinical factors, has been shown between hospitals, from region to region, and among various countries. Despite the lack of direct evidence for the benefit of VCFs for any indication, it is appropriate to insert a retrievable VCF in patients with a recent proximal deep vein thrombosis and an absolute contraindication to therapeutic anticoagulation and then to remove the filter once the bleeding risk decreases and the patient has been anticoagulated. Unfortunately, a high proportion of retrievable filters are not removed, even after the reason for their placement has long passed. Retrievable filters are associated with substantial rates of complications if they are not removed, including penetration of the vena caval wall, fracture and embolization of filter fragments, and caval occlusion. Patient safety priorities and medical-legal concerns mandate careful selection of patients for VCF placement and removal shortly after anticoagulation has been initiated.
Graft versus tumor effects and why people relapse
Authors: Falkenburg J. H. Frederik , Jedema Inge 
Published: April 2019

Abstract
Graft-versus-tumor (GVT) reactivity mediated by donor T cells in the context of allogeneic stem cell transplantation (alloSCT) is one of the most potent forms of cellular immunotherapy. The antitumor effect against hematologic malignancies is mediated by a polyclonal T-cell response targeting polymorphic antigens expressed on hematopoietic tissues of the recipient, leaving donor hematopoiesis in the patient after transplantation unharmed. Fortunately, hematopoietic tissues (including malignant hematopoietic cell populations) are relatively susceptible to T-cell recognition. If, however, nonhematopoietic tissues of the recipient are targeted as well, graft-versus-host disease (GVHD) will occur. The balance between GVT and GVHD is influenced by the genetic disparity between donor and recipient, the number and origin of professional antigen-presenting cells provoking the immune response, the target antigen specificity, magnitude and diversity of the response, and the in vivo inflammatory environment, whereas inhibitory factors may silence the immune response. Manipulation of each of these factors will determine the balance between GVT and GVHD.
Cells to prevent/treat relapse following allogeneic stem cell transplantation
Authors: Dietz Andrew C. , Wayne Alan S. 
Published: April 2019

Abstract
Relapse of cancer remains one of the primary causes of treatment failure and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). A multitude of approaches have been used in the management of posttransplant relapse. This review focuses on recent data with cellular therapies designed to treat or prevent posttransplant relapse of hematologic malignancies, although many of these therapeutic approaches also have applications to solid tumors and in the nontransplant setting. Currently available cell therapies include second transplant, natural killer cells, monocyte-derived dendritic cell vaccines, and lymphocytes via donor lymphocyte infusion, antigen-primed cytotoxic T lymphocytes, cytokine-induced killer cells, marrow-infiltrating lymphocytes, and chimeric antigen receptor T cells. These treatment options offer the prospect for improved relapse-free survival after HSCT.
Aging, hematopoiesis, and the myelodysplastic syndromes
Authors: Chung Stephen S. , Park Christopher Y. 
Published: April 2019

Abstract
The aging hematopoietic system undergoes numerous changes, including reduced production of red blood cells and lymphocytes as well as a relative increase in the production of myeloid cells. Emerging evidence indicates that many of these changes are due to selection pressures from cell-intrinsic and cell-extrinsic factors that result in clonal shifts in the hematopoietic stem cell (HSC) pool, resulting in predominant HSC clones that exhibit the functional characteristics associated with HSC aging. Given the recent descriptions of clonal hematopoiesis in aged populations, the increased risk of developing hematologic malignancies in individuals with clonal hematopoiesis, and the many similarities in hematopoietic aging and acquired bone marrow failure (BMF) syndromes, such as myelodysplastic syndromes (MDS), this raises significant questions regarding the relationship between aging hematopoiesis and MDS, including the factors that regulate HSC aging, whether clonal hematopoiesis is required for the development of MDS, and even whether BMF is an inevitable consequence of aging. In this article, we will review our current understanding of these processes and the potential intersections among them.
Managing myelofibrosis (MF) that “blasts” through: advancements in the treatment of relapsed/refractory and blast-phase MF
Authors: Scherber Robyn M. , Mesa Ruben A. 
Published: April 2019

Abstract
Myelofibrosis (MF) is the most aggressive form of Philadelphia chromosome–negative myeloproliferative neoplasm, and it is complicated by severe symptom burden, thrombotic events, infections, cytopenias, and transformation to acute myeloid leukemia (AML). Ruxolitinib, the first-line therapy for symptomatic or intermediate- and high–prognostic risk MF, has improved overall survival for this population. However, approximately one-half of MF patients will discontinue ruxolitinib by the first few years of therapy due to a spectrum of resistance, intolerance, relapse, or progression to blast phase disease. Danazol, erythropoietin-stimulating agents, and spleen-directed therapies can be useful in the ruxolitinib-resistant setting. In the ruxolitinib-refractory or -intolerant setting, commercial and novel therapies, either alone or in combination with ruxolitinib, have shown clinical utility. For blast-phase MF, the recent advancements in available AML therapies have increased the options with targeted and more tolerable therapies. In this article, we will discuss our paradigm for the management of relapsed/refractory and blast-phase MF in the context of therapeutic advancements in both AML and MF.
Adolescent angst: enrollment on clinical trials
Authors: Keegan Theresa H. M. , Parsons Helen M. 
Published: April 2019

Abstract
Survival among adolescents and young adults (AYAs) ages 15 to 39 with cancer has not improved to the same extent as that of pediatric and older adult cancer patients, which is thought to relate, in part, to the lower participation of AYAs in clinical trials. Because significant efforts have been made to improve clinical trial enrollment for AYAs, we (1) present contemporary clinical trial enrollment rates by cancer type, sociodemographic characteristics, and treatment setting and (2) discuss provider-, patient-, and system-level barriers to clinical trial participation. Contemporary studies examining clinical trial enrollment among AYAs have continued to find low overall participation relative to pediatric populations, with most studies observing no significant improvements in enrollment over time. In addition to age and cancer type, enrollment varies by treatment setting, health insurance, and race/ethnicity. Access to available clinical trials may be increased by appropriate referral of AYAs to pediatric and adult specialty cancer centers with studies relevant to the AYA population because most AYAs are treated in the community setting. Even with similar access to trials, however, AYAs may be less likely to participate, and therefore, future efforts should focus on better understanding and addressing barriers to enrollment as well as improving education and outreach regarding clinical trials.
The argument for using imatinib in CML
Authors: Claudiani Simone , Apperley Jane F. 
Published: April 2019

AbstractJune 2018 was the 20th anniversary of the clinical use of the first tyrosine kinase inhibitor (TKI), imatinib, for chronic myeloid leukemia. Since then, the change in prognosis for patients with this disease is one of the major success stories of modern cancer medicine. The dilemmas that face physicians and patients are no longer only those concerned with delaying inevitable progression to the terminal blastic phase or selecting the individuals most likely to benefit from allogeneic stem-cell transplantation; rather, they are now focused also on the choice of TKI, the management of comorbidities and adverse effects, strategies to improve quality of life, and the appropriateness of a trial of therapy discontinuation. Interestingly, with 4 TKIs approved for frontline use, the choice of initial therapy continues to cause controversy, a situation made more complicated by the tantalizing prospect of treatment-free remission. In this manuscript, we will explore the factors influencing this decision and try to provide a pragmatic and clinically applicable solution.
Sequencing of therapies in relapsed follicular lymphoma
Authors: Nastoupil Loretta J. , Flowers Christopher R. , Leonard John P. 
Published: April 2019

Abstract
Follicular lymphoma (FL) is an incurable but treatable disease with vast treatment options. Despite the abundance of efficacious treatment modalities, there is no universally agreed upon standard approach to treatment, particularly in the relapsed/refractory setting. There is an increasing need for more robust and clinically available tools to risk-stratify patients and identify those likely to experience early relapse, which is currently recognized as the unmet need in FL. Additionally, the use of gene-expression profiling and next-generation sequencing techniques in recent years has led to a wealth of knowledge regarding the molecular drivers of lymphomagenesis. However, much of this knowledge is not currently available in the clinic to inform treatment decisions. Future studies are needed to generate clinically relevant predictive models adept at incorporating patient-specific and molecular features to inform management strategies along the entire disease continuum as treatment decisions should not be made in a vacuum with a one-size-fits-all approach. Sequencing of therapy in the management of relapsed FL should involve personalized decision-making for care plans that balance patient characteristics, preferences, and comorbidities with treatment-related factors such as efficacy, toxicity profile, and mechanisms of action to achieve a durable, quality remission.
Richter transformation in the era of novel agents
Authors: Ding Wei 
Published: April 2019

AbstractRecent approvals of several oral targeted agents have revolutionized chronic lymphocytic leukemia (CLL) therapy. However, CLL patients continue to progress; particularly, 4% to 20% of previously treated CLL patients undergo transformation into high-grade lymphoma. Richter transformation is defined as a transformation of CLL into aggressive lymphoma, most commonly diffuse large B-cell lymphoma. These patients typically have poor response to traditional chemotherapy used to treat de novo diffuse large B-cell lymphoma and similar or shorter overall survival (median 3-11 months) in the era of novel agents. Here, I review the contemporary literature on Richter transformation, particularly in the context of novel agents used in CLL, and discuss the management approach for these patients.
Role of the anticoagulant monitoring service in 2018: beyond warfarin
Authors: Clark Nathan P. 
Published: April 2019

Abstract
The direct oral anticoagulants (DOACs) have a wide therapeutic index, few drug interaction, no dietary interactions and do not require dose adjustment according to the results of routine coagulation testing. Despite these advantages over warfarin, the DOACs remain high risk medications. There is evidence that non-adherence, off-label dosing and inadequate care transitions during DOAC therapy increase the risk of bleeding and thromboembolic complications. Although DOACs are approved for a growing number of indications, there remain patient populations who are not good candidates. Existing expertise within an Anticoagulation Management Service (AMS) should be leveraged to optimize all anticoagulant therapies including the DOACs. The AMS can facilitate initial drug therapy selection and dose management, reinforce patient education and adherence as well as managing drug interactions and invasive procedures. In the event that a transition to warfarin is warranted, the AMS is already engaged which limits the risk of fragmented patient care and ensures that therapeutic anticoagulation is re-established in a timely manner. The AMS of the future will provide comprehensive management for all patients receiving anticoagulant medications and continue to provide anticoagulation expertise to the healthcare team.
Evaluation and management of heavy menstrual bleeding in adolescents: the role of the hematologist
Authors: O’Brien Sarah H. 
Published: April 2019

AbstractHeavy menstrual bleeding (HMB) is frequently reported by adolescents. The role of the hematologist is threefold in evaluating such patients: (1) perform a clinical and laboratory evaluation for an underlying bleeding disorder on the basis of the degree of clinical suspicion, (2) identify and manage any concomitant iron deficiency, and (3) provide input to the referring provider regarding the management of HMB, particularly for patients with identified hemostatic defects. Several clues in the menstrual history should raise suspicion for an underlying bleeding disorder, such as menses lasting >7 days, menstrual flow which soaks >5 sanitary products per day or requires product change during the night, passage of large blood clots, or failure to respond to conventional therapies. A detailed personal and family history of other bleeding symptoms should also be obtained. Iron deficiency with and without anemia is commonly found in young women with HMB. Therefore, it is important to obtain measures of hemoglobin and ferritin levels when evaluating these patients. Iron supplementation is often a key component of management in the adolescent with heavy menses and is still needed in those who have received packed red cell transfusions as a result of severe anemia. Strategies for decreasing menstrual blood flow are similar for adults and adolescents with heavy menses, with combined hormonal contraceptives recommended as first-line therapy. However, there are adolescent-specific considerations for many of these agents, and they must be incorporated into shared decision-making when selecting the most appropriate treatment.
Elite athletes and anticoagulant therapy: an intermittent dosing strategy
Authors: Moll Stephan , Berkowitz Joshua N. , Miars Christopher W. 
Published: April 2019

Abstract
Traditionally, the athlete who requires long-term anticoagulation has been told to forgo participation in contact and collision sports. However, a strategy of short-term interruption of anticoagulant therapy may be designed for some athletes, allowing them return to full athletic activity. A personalized pharmacokinetic/pharmacodynamic study of a direct oral anticoagulant (DOAC) may allow athletic participation when plasma drug concentration is minimal and resumption of treatment after the risk of bleeding sufficiently normalizes. Scientific data and uncertainties regarding this approach, as well as practical challenges in the implementation, will be discussed.
Alternative donor transplants for severe aplastic anemia
Authors: Bacigalupo Andrea 
Published: April 2019

Abstract
Allogeneic hematopoietic stem-cell transplantation remains the only curative treatment for patients with acquired severe aplastic anemia (SAA). When a matched sibling is not available, one can search for a matched unrelated donor or a cord blood unit (CB) in the international registries or, more recently, for an HLA haploidentical (HAPLO) family member. International guidelines call for a course of antithymocyte globulin (ATG) and cyclosporine before a patient with SAA receives a transplant from a donor other than an HLA identical sibling, but whether this is necessary for patients age <20 years is less clear. Here I will examine the rapid increase in HAPLO transplantations for SAA, showing encouraging early results both in children and young adults. Graft-versus-host disease prophylaxis remains of primary importance in patients with SAA, and in vivo T-cell depletion with either ATG or alemtuzumab offers a significant survival advantage. Finally, I will discuss the strong age effect, which is particularly evident at >40 and 50 years of age for reasons not entirely clear and which should be taken into account when designing a treatment strategy for a given patient.
Measuring success: utility of biomarkers in sickle cell disease clinical trials and care
Authors: Kalpatthi Ram , Novelli Enrico M. 
Published: April 2019

AbstractProgress in the care of sickle cell disease (SCD) has been hampered by the extreme complexity of the SCD phenotype despite its monogenic inheritance. While epidemiological studies have identified clinical biomarkers of disease severity, with a few exceptions, these have not been routinely incorporated in clinical care algorithms. Furthermore, existing biomarkers have been poorly apt at providing objective parameters to diagnose sickle cell crisis, the hallmark, acute complication of SCD. The repercussions of these diagnostic limitations are reflected in suboptimal care and scarcity of adequate outcome measures for clinical research. Recent progress in molecular and imaging diagnostics has heralded a new era of personalized medicine in SCD. Precision medicine strategies are particularly timely, since molecular therapeutics are finally on the horizon. This chapter will summarize the existing evidence and promising data on biomarkers for clinical care and research in SCD.