bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel agents in follicular lymphoma: choosing the best target
Authors: Sehn Laurie H. 
Published: December 2016

AbstractOutcomes in patients with follicular lymphoma (FL) have improved dramatically over the last decade. However, novel agents are greatly needed for those who exhibit treatment resistance, in order to minimize lifelong toxicity and to enable combinations that may allow us to achieve the elusive goal of cure. Biological advances have led to the discovery of a large number of potential therapeutic targets and the development of a plethora of novel agents designed to exploit these processes. Possible targets include tumor cell surface markers, key components of intracellular pathways and epigenetic mechanisms, and reactive cells of the microenvironment. Given the large number of candidate drugs and potential combinations, it will be crucial to prioritize evaluation based on sound preclinical and early clinical studies. Combinations that exploit driver mechanisms within tumor cells and target parallel pathways to minimize the development of drug resistance, as well as harness the potential of the immune system would seem most logical. In order to expedite progress, future studies will need to use innovative trial designs and employ surrogate end points. The development of validated prognostic tools to identify higher risk patients and reliable predictive markers to select subgroups most likely to benefit from targeted agents will be paramount. The potential for unexpected toxicity with novel combinations must be recognized, necessitating both short- and long-term vigilance. Finally, as a greater number of treatment options become available, optimal sequencing must be determined in order to both prolong life and maintain its quality.
Germ line mutations associated with leukemias
Authors: Porter Christopher C. 
Published: December 2016

AbstractSeveral genetic syndromes have long been associated with a predisposition to the development of leukemia, including bone marrow failure syndromes, Down syndrome, and Li Fraumeni syndrome. Recent work has better defined the leukemia risk and outcomes in these syndromes. Also, in the last several years, a number of other germ line mutations have been discovered to define new leukemia predisposition syndromes, including ANKRD26, GATA2, PAX5, ETV6, and DDX41. In addition, data suggest that a substantial proportion of patients with therapy related leukemias harbor germ line mutations in DNA damage response genes such as BRCA1/2 and TP53. Recognition of clinical associations, acquisition of a thorough family history, and high index-of-suspicion are critical in the diagnosis of these leukemia predisposition syndromes. Accurate identification of patients with germ line mutations associated with leukemia can have important clinical implications as it relates to management of the leukemia, as well as genetic counseling of family members.
Discussing and managing hematologic germ line variants
Authors: Kohlmann Wendy , Schiffman Joshua D. 
Published: December 2016

Abstract
With the introduction of genomic technologies, more hereditary cancer syndromes with hematologic malignancies are being described. Up to 10% of hematologic malignancies in children and adults may be the result of an underlying inherited genetic risk. Managing these patients with hereditary hematologic malignancies, including familial leukemia, remains a clinical challenge because there is little information about these relatively rare disorders. This article covers some of the issues related to the diagnosis and interpretation of variants associated with hereditary hematologic malignancies, including the importance of an accurate family history in interpreting genetic variants associated with disease. The challenges of screening other family members and offering the most appropriate early malignancy detection is also discussed. We now have a good opportunity to better define hereditary cancer syndromes with associated hematologic malignancies and contribute to clinically effective guidelines.
Children with rare diseases of neutrophil granulocytes: from therapeutic orphans to pioneers of individualized medicine
Authors: Klein Christoph 
Published: December 2016

AbstractNeutrophil granulocytes are the most abundant immune cells in the blood yet the pathways orchestrating their differentiation and biological function remain incompletely understood. Studying (ultra-) rare patients with monogenetic defects of neutrophil granulocytes may open new horizons to understand basic principles of hematopoiesis and innate immunity. Here, recent insights into genetic factors controlling myelopoiesis and their more general role in biology will be presented in a clinical perspective. Advances in supportive care, first and foremost the use of recombinant human granulocyte-colony stimulating factor, has made a substantial difference for the quality of life and life expectancy of patients with congenital neutropenia (CN). Up to date, the only definitive cure can be provided by transplantation of allogeneic hematopoietic stem cells. The elucidation of the underlying molecular factors contributing to defective differentiation and function of neutrophil granulocytes nurtures new ideas of targeted individualized therapies.
Mutations in AML: prognostic and therapeutic implications
Authors: DiNardo Courtney D. , Cortes Jorge E. 
Published: December 2016

Abstract
Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the proliferation and aberrant differentiation of immature clonal myeloid cells. The prognosis of AML is variable, based on clinical features such as patient age, performance status, and comorbidities, as well as leukemia-specific genetic features including cytogenetics and molecular classification. The modern application of next-generation sequencing technology has uncovered marked heterogeneity and genomic complexity within AML, based on the presence or absence of cooperating mutations within functional categories such as epigenetic regulators, cell signaling and proliferation pathways, and master hematopoietic transcription factors. Although the treatment of AML has hitherto changed little in the past 40 years, the enhanced scientific understanding of AML pathophysiology and leukemogenesis has led to the recent development of multiple targeted and selective treatment approaches, and our increasing awareness of functional AML subsets will be evermore used to inform rational and personalized treatment strategies.
Autoimmune and other acquired neutropenias
Authors: Newburger Peter E. 
Published: December 2016

Abstract
This educational review addresses the diagnostic evaluation of patients for autoimmune and other forms of acquired neutropenia, including the futility of deconstructing the overlap of chronic “autoimmune,” “benign,” and “idiopathic” categories. Isolated neutropenias caused by infection, drugs, and immunologic disorders are also addressed. Discussion of management options emphasizes a conservative approach, with largely supportive care for these mostly benign and self-limited disorders.
Frontline therapy and role of high-dose consolidation in mantle cell lymphoma
Authors: Rule Simon 
Published: December 2016

Abstract
Mantle cell lymphoma (MCL) is a rare and aggressive form of non-Hodgkin lymphoma. It is predominantly a disease of older individuals, with a median age at presentation of ∼70 years. For the majority of patients, the management revolves around immuno-chemotherapy often followed by maintenance rituximab, and at relapse, a range of options are available. For the younger patient, it is possible to be more intensive with therapy, consolidate responses with high-dose procedures, and in a few there might be the prospect of a cure. The incorporation of high-dose cytarabine into the treatment algorithm has had a major impact on outcomes, with approximately half of the patients alive at 10 years whether an autologous stem cell transplant is adopted or not. Allogeneic transplantation produces some very durable responses in the relapsed setting and has a potential role up front in the highest-risk patients. However, with the advent of Bruton tyrosine kinase inhibitor and other highly effective nontraditional chemotherapeutic approaches, there is the potential for the management of this disease to change fundamentally over the next few years.
Cellular immune responses in red blood cell alloimmunization
Authors: Zimring James C. , Hudson Krystalyn E. 
Published: December 2016

AbstractIn excess of 340 blood group antigens have now been described that vary between individuals. Thus, any unit of blood that is nonautologous represents a significant dose of alloantigen. Most blood group antigens are proteins, which differ by a single amino acid between donors and recipients. Approximately 1 out of every 70 individuals are transfused each year (in the United States alone), which leads to antibody responses to red blood cell (RBC) alloantigens in some transfusion recipients. When alloantibodies are formed, in many cases, RBCs expressing the antigen in question can no longer be safely transfused. However, despite chronic transfusion, only 3% to 10% of recipients (in general) mount an alloantibody response. In some disease states, rates of alloimmunization are much higher (eg, sickle cell disease). For patients who become alloimmunized to multiple antigens, ongoing transfusion therapy becomes increasingly difficult or, in some cases, impossible. While alloantibodies are the ultimate immune effector of humoral alloimmunization, the cellular underpinnings of the immune system that lead to ultimate alloantibody production are complex, including antigen consumption, antigen processing, antigen presentation, T-cell biology, and B-cell biology. Moreover, these cellular processes differ to some extent with regard to transfused RBCs as compared with other better-studied immune barriers (eg, infectious disease, vaccines, and solid organ transplantation). The current work focuses on illustrating the current paradigm of humoral immunity, with a specific focus on particulars of RBC alloimmunization and recent advances in the understanding thereof.
Treatment of low-risk myelodysplastic syndromes
Authors: Santini Valeria 
Published: December 2016

Abstract
The majority of myelodysplastic syndrome (MDS) patients belong to the International Prognostic Scoring System (IPSS) and IPSS-revised (IPSS-R) lower-risk categories. Their precise diagnostics and prognostic stratification is often a challenge, but may ensure the optimization of therapy. The availability of diverse treatment options has significantly improved the quality of life and survival of this group of patients. Anemia is the most relevant cytopenia in terms of frequency and symptoms in lower-risk MDS, and may be treated successfully with erythropoietic stimulating agents, provided a careful selection is performed on the basis of IPSS-R, endogenous erythropoietin levels, and transfusion independence. Doses and duration of therapy of erythropoietic-stimulating agents (ESAs) are critical to determine efficacy. In case a patient fails ESA treatment, the available options may include lenalidomide (approved for del5q positive cases), hypomethylating agents, and a rather large number of experimental agents, whose clinical trials should be offered to a larger number of MDS patients. The choice for second-line treatment must take into account biologic, cytogenetic, and molecular-identified characteristics of individual patients, as well as frailty and comorbidities. Other cytopenias are less frequently presenting as isolated. Specific therapy for thrombocytopenia has been proposed in experimental clinical trials with thrombomimetic agents that have shown good efficacy, but raised some safety concern. Although neutropenia is targeted symptomatically with growth factor supportive care, the immunosuppressive treatments are indicated mainly for pancytopenic, hypoplastic lower-risk MDS; they are not widely used because of their toxicity, despite the fact that they may induce responses. Finally, hematopoietic stem cell transplant is the curative option also for lower-risk MDS and timing should be carefully evaluated, balancing toxicity and the possibility of survival advantage. Finally, even when considered suitable for lower-risk MDS, transplant application is limited to the rarer fit and younger MDS patient.
Myelofibrosis: to transplant or not to transplant?
Authors: Devlin Rebecca , Gupta Vikas 
Published: December 2016

Abstract
Hematopoietic cell transplantation (HCT) is the only curative therapeutic modality for myelofibrosis (MF) at present. The optimal timing of HCT is not known in the presence of wider availability of less risky nontransplant therapies such as JAK 1/2 inhibitors. Careful review of patient, disease, and transplant-related factors is required in the appropriate selection of HCT vs the best available nontransplant therapies. We highlight some of the relevant issues and positioning of HCT in light of evolving data on JAK 1/2 inhibitors. The goal of this study is to provide the reader with updated evidence of HCT for MF, recognizing that knowledge in this area is limited by the absence of comparative studies between HCT and nontransplant therapies. Prospective studies are needed for better information on: the determination of optimal timing and conditioning regimens, the best way to integrate JAK inhibitors in the HCT protocols, and the impact of JAK inhibitors on graft-versus-host disease.
Ph-like acute lymphoblastic leukemia
Authors: Tran Thai Hoa , Loh Mignon L. 
Published: December 2016

Abstract
Philadelphia chromosome–like acute lymphoblastic leukemia (Ph-like ALL) is a newly identified high-risk (HR) B-lineage ALL subtype, accounting for ∼15% of children with National Cancer Institute–defined HR B-ALL. It occurs more frequently in adolescents and adults, having been reported in as much as 27% of young adults with ALL between 21 and 39 years of age. It exhibits adverse clinical features, confers a poor prognosis, and harbors a diverse range of genetic alterations that activate cytokine receptor genes and kinase signaling pathways, making it amenable to treatment with tyrosine kinase inhibitor (TKI) therapy. Multiple groups are currently conducting clinical trials to prospectively screen patients with Ph-like ALL and incorporate the relevant TKI for those harboring ABL-class gene rearrangements or those with JAK-STAT pathway alterations. The success of combinatorial treatment of TKI with chemotherapy in the setting of Ph-positive ALL suggests that this approach may similarly improve outcomes for patients with Ph-like ALL. Hence, Ph-like ALL illustrates the modern treatment paradigm of precision medicine and presents unique opportunities for harnessing international collaborations to further improve outcomes for patients with ALL.
Reversing vitamin K antagonists: making the old new again
Authors: Eichinger Sabine 
Published: December 2016

Abstract
Vitamin K antagonists (VKAs) are commonly used for the prevention and treatment of thrombotic disorders. The response to VKAs is highly variable due to their specific interaction with the vitamin K cycle, and hence interference with hepatic synthesis of vitamin K-dependent coagulation factors. Monitoring the anticoagulant effect of VKAs by assessing the patient’s international normalized ratio (INR) is essential because complications are closely related to the intensity of anticoagulation. Treatment with VKAs contains a substantial risk of bleeding with a high case fatality rate. Reversal of VKAs is required in case of bleeding or a supratherapeutic INR, but also prior to high-risk surgery or interventions. Choice of methods to reverse VKAs depends on whether or not the patient is bleeding or is in need of an urgent procedure, and has to be based on the pharmacokinetic and pharmacodynamic properties of the VKA. Reversal strategies include withholding the VKA, administration of vitamin K1, and substitution of vitamin K-dependent procoagulant factors, and need to be combined with measures according to general bleeding management.
What to do after the bleed: resuming anticoagulation after major bleeding
Authors: Witt Daniel M. 
Published: December 2016

Abstract
Resuming anticoagulation therapy after a potentially life-threatening bleeding complication evokes high anxiety levels among clinicians and patients trying to decide whether resuming oral anticoagulation to prevent devastating and potentially fatal thromboembolic events or discontinuing anticoagulation in hopes of reducing the risk of recurrent bleeding is best. The available evidence favors resumption of anticoagulation therapy for gastrointestinal tract bleeding and intracranial hemorrhage survivors, and it is reasonable to begin postbleeding decision making with resuming anticoagulation therapy as the default plan. After considering factors related to the index bleeding event, the underlying thromboembolic risk, and comorbid conditions, a decision to accept or modify the default plan can be made in collaboration with other care team members, the patient, and their caregivers. Although additional information is needed regarding the optimal timing of anticoagulation resumption, available evidence indicates that waiting ∼14 days may best balance the risk of recurrent bleeding, thromboembolism, and mortality after gastrointestinal tract bleeding. When to resume anticoagulation after intracranial hemorrhage is less clear, but most studies indicate that resumption within the first month of discharge is associated with better outcomes.
Sickle cell disease: an inherited thrombophilia
Authors: Wun Ted , Brunson Ann 
Published: December 2016

Abstract
Activation of the hemostatic system occurs in patients with sickle cell disease. The extent to which this activation contributes to sickle cell pathophysiology is uncertain. Clinical trials of anticoagulants or platelet inhibitors have demonstrated the ability to decrease biomarkers of hemostatic activation, but this has generally not resulted in improvement in clinically relevant outcomes. Venous thromboembolism (VTE: deep venous thrombosis and pulmonary embolism) has been until recently an underappreciated complication of sickle cell disease, with incident event and recurrence rates consistent with a strong thrombophilia. There is no strong evidence that management should differ than for other patients with VTE, with the possible exception that secondary prophylaxis be extended regardless of provocation, given the persistent strong thrombophilic state.
What is the role of an extended half-life product in immune tolerance induction in a patient with severe hemophilia A and high-titer inhibitors?
Authors: Janbain Maissaa , Pipe Steven 
Published: December 2016

Abstract
A 10-year-old boy presents with a history of severe hemophilia A and high-titer inhibitor that had failed high-dose immune tolerance induction (ITI) with a recombinant factor VIII (rFVIII) product and a plasma-derived FVIII product. You are asked by his mother whether he should be tried on ITI with an extended half-life product, in particular, consideration of a rFVIIIFc concentrate.
What have we learned from large population studies of von Willebrand disease?
Authors: Montgomery Robert R. , Flood Veronica H. 
Published: December 2016

AbstractVon Willebrand factor (VWF) is a critical regulator of hemostatic processes, including collagen binding, platelet adhesion, and platelet aggregation. It also serves as a carrier protein to normalize plasma factor VIII synthesis, release, and survival. While VWF protein measurements by immunoassay are reasonably comparable between institutions, the measurement of VWF ristocetin cofactor activity (VWF:RCo) has significant variability. Other tests of VWF function, including collagen binding or platelet glycoprotein IIb-IIIa binding, are not universally available, yet these functional defects may cause major bleeding even with normal VWF antigen (VWF:Ag) and VWF:RCo assays. This results in both the overdiagnosis and underdiagnosis of VWD. Newer assays of VWF function (using recombinant glycoprotein Ib rather than whole platelets) have been developed that may improve interlaboratory variability. Some of these tests are not uniformly available and may not be licensed in the United States. Large longitudinal studies of VWF in von Willebrand disease (VWD) patients are not available. Patients are sometimes diagnosed with a single diagnostic VWF panel. Plasma VWF levels increase with age, but it is not clear if this results in less bleeding or whether different normal ranges should be used to identify age-related decreases in VWF. In order to quantitatively compare bleeding symptoms in VWD patients and normal individuals, recent studies in the European Union, Canada, United Kingdom, Holland, and the United States have used semiquantitative bleeding assessment tools (BATs). Even with careful centralized testing, including functional assays of VWF, addition of a BAT does not solve all of the problems with VWD diagnosis. No matter where the line is drawn for diagnosis of VWD, VWF is still a continuous variable. Thus, VWD can be a severe hemorrhagic disease requiring frequent treatment or a mild condition that may not be clinically relevant. As will be discussed by Dr. Goodeve in her presentation, genetics has helped us to diagnose type 2 functional variants of VWD but has not been helpful for the many patients who are at the interface of normal and low VWF and carry the possible diagnosis of type 1 VWD. The hematologist’s management of patients with reduced levels of VWF still requires both the art and science of clinical medicine.
New treatment approaches to von Willebrand disease
Authors: Lavin Michelle , O’Donnell James S. 
Published: December 2016

Abstract
von Willebrand disease (VWD) is the commonest inherited bleeding disorder and results from either a quantitative or qualitative deficiency in the plasma glycoprotein von Willebrand factor (VWF). Recent large cohort studies have significantly enhanced our understanding of the molecular mechanisms involved in the pathogenesis of VWD. In contrast, however, there have been relatively few advances in the therapeutic options available for the treatment of bleeding in patients with VWD. Established treatment options include tranexamic acid, 1-deamino-8-d-arginine vasopressin (DDAVP), and plasma-derived VWF concentrates. In addition, a recombinant VWF has also recently been developed. In this review, we focus on how recent insights into the clinical and molecular aspects underpinning VWD are already beginning to influence treatment in the clinic. For example, a number of different bleeding assessment tools (BATs) have been developed to objectively assess bleeding symptoms in patients with VWD. Interestingly, however, these BAT scores may also have an important role to play in predicting bleeding risk in VWD. Furthermore, recent studies have demonstrated that enhanced VWF clearance plays a critical role in the etiology of both type 1 and type 2 VWD. These findings have direct translational relevance with respect to the use of DDAVP in patients with VWD. As understanding of the mechanisms involved in VWD pathogenesis continues to advance, novel treatment options are likely to emerge. Critically, however, large adequately powered and stratified clinical trials will be required to address the outstanding questions that remain regarding VWD treatment optimization.