bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acquired bleeding disorders in the elderly
Authors: Kruse-Jarres Rebecca 
Published: September 2016

Abstract
The hemostatic balance changes with advancing age which may be due to factors such as platelet activation, increase of certain clotting factor proteins, slowing of the fibrinolytic system, and modification of the endothelium and blood flow. Generally, this predisposes the elderly to thrombosis rather than bleeding. It often necessitates antiplatelet or anticoagulation therapy, which can cause significant bleeding problems in an aging population. Additionally, changing renal function, modification in immune regulation, and a multitude of other disease processes, can give rise to acquired bleeding disorders. Bleeding can prove difficult to treat in a dynamic environment and in a population that may have underlying thrombotic risk factors.
This article discusses some specific challenges of acquired bleeding arising in the elderly. The use of anticoagulation and nonsteroidal anti-inflammatory medications is prevalent in the treatment of the elderly and predisposes them to increased bleeding risk as their physiology changes. When prescribing and monitoring these therapies, it is exceedingly important to weigh thrombotic versus bleeding risks. There are additional rare acquired bleeding disorders that predominantly affect the elderly. One of them is acquired hemophilia, which is an autoimmune disorder arising from antibodies against factor VIII. The treatment challenge rests in the use of hemostatic agents in a population that is already at increased risk for thrombotic complications. Another rare disorder of intensifying interest, acquired von Willebrand syndrome, has a multitude of etiologic mechanisms. Understanding the underlying pathophysiology is essential in making a treatment decision for this disorder.
Bleeding complications in immune thrombocytopenia
Authors: Arnold Donald M. 
Published: September 2016

Abstract
Bleeding manifestations in patients with immune thrombocytopenia (ITP) range from mild skin bruises to life-threatening intracranial hemorrhage (ICH). Severe bleeding is distinctly uncommon when the platelet count is >30 × 109/L and usually only occurs when the platelet count falls <10 × 109/L. Based on estimates from clinical studies, ITP registries and administrative databases, the frequency of ICH in patients with ITP is ∼0.5% in children and 1.5% in adults. Estimates of severe (non-ICH) bleeding are difficult to obtain because of the lack of standardized case definitions; the lack of a universally accepted, ITP-specific bleeding assessment tool; and the omission of reporting bleeding outcomes in many clinical studies. In practice, the presence of bleeding should dictate whether or not treatment is needed because many patients, especially children, can be safely managed with observation alone. Guiding principles for the management of ITP, based on the bleeding risk are: (1) Decide when treatment is needed and when it can safely be withheld; (2) for patients with chronic ITP, use the least toxic treatment at the lowest dose; (3) emergency treatment of severe thrombocytopenia-associated bleeding requires combination therapy; and (4) early aggressive therapy may result in durable platelet count responses.
Coagulopathy in liver disease: a balancing act
Authors: Kujovich Jody L. 
Published: September 2016

Abstract
Liver disease results in complex alterations of all 3 phases of hemostasis. It is now recognized that hemostasis is rebalanced in chronic liver disease. The fall in clotting factor levels is accompanied by a parallel fall in anticoagulant proteins. High von Willebrand factor levels counteract defects in primary hemostasis. Conventional coagulation tests do not fully reflect the derangement in hemostasis and do not accurately predict the risk of bleeding. Global coagulation assays (thrombin generation, thromboelastography) reflect the interaction between procoagulant factors, anticoagulant factors, platelets, and the fibrinolytic system and show promise for assessing bleeding risk and guiding therapy. These assays are not yet commercially approved or validated. Prevention of bleeding should not be aimed at correcting conventional coagulation tests. Thrombopoietin receptor agonists were shown to increase the platelet count in cirrhotic patients undergoing invasive procedures but may increase the risk of thrombosis. Rebalanced hemostasis in liver disease is precarious and may be tipped toward hemorrhage or thrombosis depending on coexisting circumstantial risk factors. Bacterial infection may impair hemostasis in cirrhosis by triggering the release of endogenous heparinoids. There are no evidence-based guidelines for hemostatic therapy of acute hemorrhage in liver disease. There is currently inadequate evidence to support the use of recombinant FVIIa, prothrombin complex concentrates, or tranexamic acid in acute variceal or other hemorrhage.
Molecular monitoring in CML and the prospects for treatment-free remissions
Authors: Deininger Michael W. 
Published: September 2016

Abstract
Monitoring treatment responses in chronic myeloid leukemia (CML) is based on complete blood counts (CBCs) to determine hematologic response, karyotyping of bone marrow metaphase cells to delineate cytogenetic response and quantitative reverse transcription polymerase chain reaction (qPCR) to quantify expression of BCR-ABL1 mRNA (molecular response; MR) in peripheral blood. Fluorescence in situ hybridization (FISH) to identify BCR-ABL1 in interphase nuclei and mutational analysis of the BCR-ABL1 kinase domain (KD) are used in certain clinical circumstances. As most patients treated with tyrosine kinase inhibitors (TKIs) achieve complete cytogenetic responses (CCyRs), qPCR with its increased sensitivity and dynamic range has become the main tool used to monitor CML patients. Landmark analyses of large TKI trials have established MR milestones that identify patients with high risk of failure, are the basis of consensus management guidelines, and have led to a strong push toward qPCR test standardization. Today many laboratories report BCR-ABL1 qPCR results on the international scale (IS), a system based on the conversion of laboratory-specific numerical values to conform to a universal scale. The fact that qPCR is technically demanding and liable to assay variations poses considerable challenges for its routine clinical use. This is important as the prevalence of patients on chronic TKI therapy increases and critical clinical decisions are made based on qPCR results, for example if discontinuation of TKI therapy should be considered. Here we will review the current state of molecular monitoring in CML, focusing on qPCR, the definition of TKI failure and the results of TKI discontinuation studies.
Maintenance therapy for multiple myeloma in the era of novel agents
Authors: Facon Thierry 
Published: September 2016

Abstract
Despite many recent advances in the treatment of multiple myeloma, the course of the disease is characterized by a repeating pattern of periods of remission and relapse as patients cycle through the available treatment options. Evidence is mounting that long-term maintenance therapy may help suppress residual disease after definitive therapy, prolonging remission and delaying relapse. For patients undergoing autologous stem cell transplantation (ASCT), lenalidomide maintenance therapy has been shown to improve progression-free survival (PFS); however, it is still unclear whether this translates into extended overall survival (OS). For patients ineligible for ASCT, continuous therapy with lenalidomide and low-dose dexamethasone was shown to improve PFS and OS (interim analysis) compared with a standard, fixed-duration regimen of melphalan, prednisone, and thalidomide in a large phase 3 trial. Other trials have also investigated thalidomide and bortezomib maintenance for ASCT patients, and both agents have been evaluated as continuous therapy for those who are ASCT ineligible. However, some important questions regarding the optimal regimen and duration of therapy must be answered by prospective clinical trials before maintenance therapy, and continuous therapy should be considered routine practice. This article reviews the available data on the use of maintenance or continuous therapy strategies and highlights ongoing trials that will help to further define the role of these strategies in the management of patients with newly diagnosed multiple myeloma.
Surveying the landscape of MDS/MPN research: overlap among the overlap syndromes?
Authors: Padron Eric 
Published: September 2016

Abstract
The myelodysplastic/myeloproliferative neoplasms (MDS/MPNs) lie at the interphase of phenotypically opposing bone marrow malignancies. They are characterized by concomitant features of bone marrow failure and myeloproliferation and are generally associated with a poor prognosis. Although much is unknown with respect to the clinical course and molecular biology of MDS/MPNs, emerging research is beginning to uncover the key defining characteristics of this designation. In this review, we will discuss the features of MDS/MPN diseases that unify there clinical and molecular course and those that define distinct disease entities. We will discuss advances in genetics and MDS/MPN modeling, as well as translational discoveries that are anticipated to inform the diagnosis, prognostication, and treatment of MDS/MPNs in the near future.
Management of adult Ph-positive acute lymphoblastic leukemia
Authors: Chiaretti Sabina , Foà Robin 
Published: September 2016

Abstract
Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) has been regarded for decades as the ALL subgroup with the worse outcome. It represents the most frequent genetic subtype of adult ALL, and increases progressively with age. The introduction of tyrosine kinase inhibitors (TKIs) has enabled to obtain complete hematologic remissions (CHRs) in virtually all patients, including the elderly, to improve disease-free survival and overall survival, as well as to increase the percentage of patients who can undergo an allogeneic stem cell transplant (allo-SCT).
The current management of adult Ph+ ALL patients relies on the use of a TKI with or without chemotherapy followed by an allo-SCT, which still remains the only curative option. Minimal residual disease screening is permitting not only a better stratification of patients, but has also allowed to reconsider the role of autologous stem cell transplant for a set of patients who do not have a donor or are not eligible for an allo-SCT. At present, clinical challenges are represented by the emergence of resistant mutations, particularly the gatekeeper T315I, for which alternative approaches, comprising novel TKIs or therapies based on the combination of TKI with immunotherapeutic strategies, are being considered in order to overcome resistance.
Managing older patients with hemophilia
Authors: Angelini Dana , Sood Suman L. 
Published: September 2016

AbstractWith access to safe factor products, the life expectancy of persons with hemophilia (PWHs) has increased almost 10-fold over the past 7 decades. Unfortunately, hand in hand with this success comes the burden of aging. As PWHs age, they are subject to develop many of the same risk factors as the general population, including increasing rates of hypertension, obesity, and diabetes. Such comorbidities predispose them to chronic diseases, such as cardiovascular disease and chronic kidney disease, although how their coagulopathy affects the expression of these conditions remains unclear. The older hemophilia population faces additional challenges, such as chronic joint arthropathy, which provokes falls and fractures, and complications related to HIV and hepatitis C infections, which greatly affect the incidence of cancer and liver disease. In light of the paucity of evidence-based guidelines to direct therapy, a new challenge has arisen for hematologists to optimally manage these complex age-related issues. In general, elderly PWHs should be treated similarly to their peers without hemophilia, with the addition of factor replacement therapy as appropriate. Primary prevention of risk factors should be emphasized, and close coordination between specialties is essential. This review will focus on common complications affecting the older hemophilia population, including cardiovascular disease, malignancy, liver disease, renal insufficiency, and joint disease.
How can we improve on the already impressive results in pediatric ALL?
Authors: Thomas Angela 
Published: September 2016

Abstract
The past 70 years have seen childhood acute lymphoblastic leukemia move from a fatal disease with a survival of barely 4 months to a curable disease in >85% of patients. It has become clear that as treatment has intensified, more children are cured but at the expense of increased toxicity which for some can cause significant long-term morbidity and even mortality. The drive in more recent years has been to identify sensitive markers of disease and response to treatment to allow a reduction in therapy in those who do not require it and more intensive treatment in those who do. Clinical characteristics have been used to stratify patients into different risk groups and this, coupled with following response at a molecular level, has done much to tailor treatment to the patient. Considerable research has been focused on the molecular characteristics of the leukemia itself to elucidate the biologic mechanisms underlying both the disease and the comparative or absolute resistance of some types of leukemia. These molecular markers can also act as targets for novel therapies, which require newer trial methodologies to prove their utility. There has been less focus on the biology of the patient but it is clear that some patients are more susceptible to adverse events and toxicities than others. Through the use of pharmacogenomics, modification to therapy may be appropriate in certain patients based on their genetic profile. As novel therapies become available, suitable controlled trials in children are essential for their safe use in this population and will ensure that children are not denied timely access to advances in treatment.
Optimizing hydroxyurea therapy for sickle cell anemia
Authors: Ware Russell E. 
Published: September 2016

Abstract
Hydroxyurea has proven efficacy in numerous clinical trials as a disease-modifying treatment for patients with sickle cell anemia (SCA) but is currently under-used in clinical practice. To improve the effectiveness of hydroxyurea therapy, efforts should be directed toward broadening the clinical treatment indications, optimizing the daily dosage, and emphasizing the benefits of early and extended treatment. Here, various issues related to hydroxyurea treatment are discussed, focusing on both published evidence and clinical experience. Specific guidance is provided regarding important but potentially unfamiliar aspects of hydroxyurea treatment for SCA, such as escalating to maximum tolerated dose, treating in the setting of cerebrovascular disease, switching from chronic transfusions to hydroxyurea, and using serial phlebotomy to alleviate iron overload. Future research directions to optimize hydroxyurea therapy are also discussed, including personalized dosing based on pharmacokinetic modeling, prediction of fetal hemoglobin responses based on pharmacogenomics, and the risks and benefits of hydroxyurea for non-SCA genotypes and during pregnancy/lactation. Another critical initiative is the introduction of hydroxyurea safely and effectively into global regions that have a high disease burden of SCA but limited resources, such as sub-Saharan Africa, the Caribbean, and India. Final considerations emphasize the long-term goal of optimizing hydroxyurea therapy, which is to help treatment become accepted as standard of care for all patients with SCA.
Spanning the canyon between stem cell transplantation and palliative care
Authors: Roeland Eric , Ku Grace 
Published: September 2016

Abstract
Stem cell transplantation (SCT) and palliative care (PC) may initially appear to be distant extremes in the continuum of care of patients with hematologic malignancies, opposed by multiple obstacles preventing their integration. Rather, we will posit that both fields share many similarities and have much to learn from one another. PC has increasing relevance in cancer care given recent studies that link PC to improved quality-of-life, survival, and decreased cost of care. Understanding modern conceptualizations of PC and its role within SCT is key. Through the report of a single academic medical center experience with an integrated SCT and PC model over the last decade, we will discuss future opportunities for strengthening collaboration between SCT and PC. PC in SCT should be considered from the day of diagnosis and tied to need, not to prognosis.
Patient-reported outcomes in clinical practice
Authors: Dobrozsi Sarah , Panepinto Julie 
Published: September 2016

AbstractPatient-reported outcome (PRO) measurement plays an increasingly important role in health care and understanding health outcomes. PROs are any report of a patient's health status that comes directly from the patient, and can measure patient symptoms, patient function, and quality-of-life. PROs have been used successfully to assess impairment in a clinical setting. Use of PROs to systematically quantify the patient experience provides valuable data to assist with clinical care; however, initiating use of PROs in clinical practice can be daunting. Here we provide suggestions for implementation of PROs and examples of opportunities to use PROs to tailor individual patient therapy to improve patient outcomes, patient–physician communication, and the quality of care for hematology/oncology patients.
Zebras and hen's teeth: recognition and management of rare T and NK lymphomas
Authors: Mehta–Shah Neha , Horwitz Steven 
Published: September 2016

Abstract
Although all the peripheral T-cell lymphomas are uncommon, there are some entities that are truly rare. Subtypes, such as enteropathy-associated T-cell lymphoma, hepatosplenic T-cell lymphoma, extranodal NK/T-cell lymphoma, and subcutaneous panniculitis-like T-cell lymphoma, have an approximate annual incidence in United States of <500 each. In these very rare subtypes, there is limited data to guide clinical decision-making. As such, our treatment decisions are often based on extrapolation, case series, personal experience, and biases. We summarize the existing data regarding initial management of these entities and compare how that management follows paradigms established for the more common T-cell lymphomas.
Mechanical circulatory support: balancing bleeding and clotting in high-risk patients
Authors: Baumann Kreuziger Lisa , Massicotte M. Patricia 
Published: September 2016

Abstract
Mechanical circulatory support (MCS) provides a bridge to heart transplant in children and adults with life-threatening heart failure and sustains patients ineligible for transplant. Extracorporeal membrane oxygenation (ECMO) provides temporary support for patients in cardiac or pulmonary failure through external gas exchange and continuous flow of blood. Because the median time to heart transplant exceeds event-free time on ECMO, pulsatile left ventricular assist devices (LVADs) are used to support infants and children. Continuous flow LVADs are preferred in adolescents and adults due to increased pump durability and improved overall survival. The shear stress created by the mechanical pumps cause changes in the hematologic system; acquired von Willebrand syndrome occurs in almost all patients treated with MCS. Despite the improvements in survival, major bleeding occurs in one-third of patients with a LVAD and ischemic stroke and LVAD thrombosis can affect 12% of adults and 29% of children. An antithrombotic strategy to mitigate LVAD bleeding and thrombotic complications has been tested in a randomized trial in children, but intensity of antithrombotic therapy in adults varies widely. Consensus guidelines for antithrombotic therapy during ECMO were created due to significant differences in management across centers. Because of the high risk for both bleeding and thrombotic complications, experts in hemostasis can significantly impact care of patients requiring mechanical circulatory support and are a necessary part of the management team.
Checkpoint blockade in lymphoma
Authors: Armand Philippe 
Published: September 2016

AbstractImmune checkpoint blockade therapy (CBT) was born of the combination of several elements: the understanding of some of the important immune regulation pathways in humans; the recognition that tumors can engage those pathways to evade immune responses; and the clinical development of monoclonal antibodies targeting checkpoint receptors to restore effective anti-tumor immunity. This form of therapy, focused to date mostly on the cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed-death 1 (PD-1) pathways, has already revolutionized the treatment of several solid tumors. Hematologic malignancies (HMs) offer a promising testing ground for this strategy, and several trials have already demonstrated evidence of therapeutic activity with checkpoint blockade, especially in lymphoma. This review will discuss the current clinical results of CBT in lymphoma in the context of their scientific underpinning, and build from this summary a projection of how the field may evolve in the near future.
EnsCat: clustering of categorical data via ensembling
Authors: Clarke Bertrand S. , Amiri Saeid , Clarke Jennifer L. 
Published: September 2016

Abstract
Background
Clustering is a widely used collection of unsupervised learning techniques for identifying natural classes within a data set. It is often used in bioinformatics to infer population substructure. Genomic data are often categorical and high dimensional, e.g., long sequences of nucleotides. This makes inference challenging: The distance metric is often not well-defined on categorical data; running time for computations using high dimensional data can be considerable; and the Curse of Dimensionality often impedes the interpretation of the results. Up to the present, however, the literature and software addressing clustering for categorical data has not yet led to a standard approach.

Results
We present software for an ensemble method that performs well in comparison with other methods regardless of the dimensionality of the data. In an ensemble method a variety of instantiations of a statistical object are found and then combined into a consensus value. It has been known for decades that ensembling generally outperforms the components that comprise it in many settings. Here, we apply this ensembling principle to clustering.
We begin by generating many hierarchical clusterings with different clustering sizes. When the dimension of the data is high, we also randomly select subspaces also of variable size, to generate clusterings. Then, we combine these clusterings into a single membership matrix and use this to obtain a new, ensembled dissimilarity matrix using Hamming distance.

Conclusions
Ensemble clustering, as implemented in and called , gives more clearly separated clusters than other clustering techniques for categorical data. The latest version with manual and examples is available at https://github.com/jlp2duke/EnsCat.