bluuebunny/crossref_metadata_2025_split huggingface dataset:
Incidental venous thromboembolism: is anticoagulation indicated?
Authors: Di Nisio Marcello , Carrier Marc 
Published: April 2019

Abstract
Patients with cancer have a high risk of venous thromboembolism (VTE) and about one-half of these events are incidentally detected. The prognosis of incidental VTE appears to be similar to symptomatic events, with comparably high rates of recurrent VTE in this patient population. In the absence of major contraindications, anticoagulant treatment with low-molecular-weight heparin for 3 to 6 months is generally recommended for incidental proximal deep vein thrombosis as well as for incidental pulmonary embolism that involves multiple subsegmental or more proximal pulmonary arteries. The decision of whether to extend treatment beyond 3 to 6 months should be evaluated on a case-by-case basis after periodic reassessment of the risks factors for bleeding and recurrent VTE while also taking into account patient preferences. The clinical relevance of a single incidental subsegmental pulmonary embolism without concomitant deep vein thrombosis is uncertain and either a watchful approach or a shorter course of anticoagulation to minimize the bleeding risk may also be considered. Preliminary evidence suggests that anticoagulation treatment may be beneficial for cancer patients with incidental distal deep vein thrombosis or incidental splanchnic vein thrombosis.
Thrombocytopenia in pregnancy
Authors: Cines Douglas B. , Levine Lisa D. 
Published: April 2019

Abstract
Thrombocytopenia develops in 5% to 10% of women during pregnancy or in the immediate postpartum period. A low platelet count is often an incidental feature, but it might also provide a biomarker of a coexisting systemic or gestational disorder and a potential reason for a maternal intervention or treatment that might pose harm to the fetus. This chapter reflects our approach to these issues with an emphasis on advances made over the past 5 to 10 years in understanding and managing the more common causes of thrombocytopenia in pregnancy. Recent trends in the management of immune thrombocytopenia translate into more women contemplating pregnancy while on treatment with thrombopoietin receptor agonists, rituximab, or mycophenylate, which pose known or unknown risks to the fetus. New criteria to diagnose preeclampsia, judicious reliance on measurement of ADAMTS13 to make management decisions in suspected thrombotic thrombocytopenic purpura, new evidence supporting the efficacy and safety of anticomplement therapy for atypical hemolytic uremic syndrome during pregnancy, and implications of thrombotic microangiopathies for subsequent pregnancies are evolving rapidly. The goals of the chapter are to help the hematology consultant work through the differential diagnosis of thrombocytopenia in pregnancy based on trimester of presentation, severity of thrombocytopenia, and coincident clinical and laboratory manifestations, and to provide guidance for dealing with some of the more common and difficult diagnostic and management decisions.
Should we diagnose and treat distal deep vein thrombosis?
Authors: Robert-Ebadi Helia , Righini Marc 
Published: April 2019

Abstract
Ultrasound series report that isolated distal deep vein thrombosis (DVT), also known as calf DVT, represents up to 50% of all lower-limb DVTs and, therefore, is a frequent medical condition. Unlike proximal DVT and pulmonary embolism, which have been studied extensively and for which management is well standardized, much less is known about the optimal management of isolated calf DVT. Recent data arising from registries and nonrandomized studies have suggested that most distal DVTs do not extend to the proximal veins and have an uneventful follow-up when left untreated. These data had some impact on the international recommendations that recently stated that ultrasound surveillance instead of systematic therapeutic anticoagulation might be an option for selected low-risk patients. However, robust data from randomized studies are scarce. Only 5 randomized trials assessing the need for anticoagulation for calf DVT have been published. Many of these trials had an open-label design and were affected by methodological limitations. The only randomized placebo-controlled trial included low-risk patients (outpatients without cancer or previous venous thromboembolism [VTE]) and was hampered by limited statistical power. Nevertheless, data from this trial confirmed that the use of therapeutic anticoagulation in low-risk patients with symptomatic calf DVT is not superior to placebo in reducing VTE but is associated with a significantly higher risk of bleeding. Further randomized studies are needed to define the best therapy for high-risk patients (inpatients, patients with active cancer, or patients with previous VTE) and the optimal dose and duration of treatment.
Optimizing therapy for mantle cell lymphoma
Authors: Martin Peter 
Published: April 2019

AbstractMost people with mantle cell lymphoma (MCL) present with diffuse adenopathy and benefit from early initiation of rituximab and high-dose cytarabine- or bendamustine-based therapies. Some patients, however, present with primarily nonnodal disease that can follow either an indolent or a rapidly progressive, treatment-resistant clinical course. Rarely, patients present with explosive disease that can be challenging to manage and often involves the central nervous system. New agents with improved therapeutic indices facilitate treatment while maintaining quality of life, but also present new complications at the time of treatment failure. Although uncommon presentations are not new to clinicians who treat MCL, the increasing clarity of underlying biology and prognostic implications may help us develop more specialized treatment strategies.
Signaling pathways and immune evasion mechanisms in classical Hodgkin lymphoma
Authors: Liu W. Robert , Shipp Margaret A. 
Published: April 2019

Abstract
Classical Hodgkin lymphoma (cHL) is an unusual B-cell–derived malignancy in which rare malignant Hodgkin and Reed-Sternberg (HRS) cells are surrounded by an extensive but ineffective inflammatory/immune cell infiltrate. This striking feature suggests that malignant HRS cells escape immunosurveillance and interact with immune cells in the cancer microenvironment for survival and growth. We previously found that cHLs have a genetic basis for immune evasion: near-uniform copy number alterations of chromosome 9p24.1 and the associated PD-1 ligand loci, CD274/PD-L1 and PDCD1LG2/PD-L2, and copy number–dependent increased expression of these ligands. HRS cells expressing PD-1 ligands are thought to engage PD-1 receptor–positive immune effectors in the tumor microenvironment and induce PD-1 signaling and associated immune evasion. The genetic bases of enhanced PD-1 signaling in cHL make these tumors uniquely sensitive to PD-1 blockade.
Emerging role of novel therapies in Hodgkin lymphoma: proceed with caution
Authors: Bartlett Nancy L. 
Published: April 2019

AbstractBased on very high response rates in the relapsed and refractory setting, brentuximab vedotin and the programmed cell death protein 1 (PD-1) inhibitors, nivolumab and pembrolizumab, have quickly been incorporated into clinical trials for first- and second-line therapy of Hodgkin lymphoma. Preliminary data show that brentuximab vedotin alone is not adequate therapy for newly diagnosed Hodgkin lymphoma in older patients, but modestly decreases the risk of relapse when combined with adriamycin, vinblastine, and dacarbazine in patients with previously untreated advanced-stage disease. In second-line therapy, combining brentuximab vedotin with conventional chemotherapy or with PD-1 inhibitors as pretransplant salvage is associated with high overall and complete response rates, although further follow up is needed to assess whether posttransplant outcomes are improved. Although these new drugs are well tolerated when given as single agents, unexpected toxicities have been encountered with combination regimens, specifically severe pulmonary toxicity with the bleomycin and brentuximab vedotin combination and frequent infusion-related reactions. There is concern with the use of PD-1 inhibitors as first-line therapy due to the theoretical potential for more frequent or severe immune-mediated toxicities in patients who have not received prior chemotherapy. Aside from these concerns, these new agents have the potential to improve outcomes for patients even further, bringing us closer to eradicating recurrent Hodgkin lymphoma.
Optimizing frontline therapy of CLL based on clinical and biological factors
Authors: Fischer Kirsten , Hallek Michael 
Published: April 2019

Abstract
The heterogeneity of the clinical course of chronic lymphocytic leukemia (CLL) ranges from an indolent course, where patients do not require therapy for many years, to a very aggressive disease, where treatment is required soon after diagnosis and relapses may occur early. The improved tools for prognostication allow predicting the outcome of patients with increasing reliability. Some markers also allow selecting more specific therapies with improved activity in the presence of certain genetic or clinical features of CLL. Of these markers, TP53 dysfunction, age, the presence of comorbidities and the immunoglobulin heavy-chain variable region gene mutational status, or serum markers such as β2-microglobulin have shown independent prognostic value in multiple prospective trials. During the last 10 years, multiple novel agents have become available. The advent of oral kinase inhibitors or Bcl-2 antagonists has provided highly effective options with acceptable toxicity. This manuscript summarizes the current evidence of the available treatment options and proposes an integrated algorithm for the frontline therapy of CLL.
How should we sequence and combine novel therapies in CLL?
Authors: Davids Matthew S. 
Published: April 2019

AbstractWith the recent approval of several effective and well-tolerated novel agents (NAs), including ibrutinib, idelalisib, venetoclax, and obinutuzumab, patients with chronic lymphocytic leukemia (CLL) have more therapeutic options than ever before. The availability of these agents is both an important advance for patients but also a challenge for practicing hematologist/oncologists to learn how best to sequence NAs, both with respect to chemoimmunotherapy (CIT) and to other NAs. The sequencing of NAs in clinical practice should be guided both by an individual patient’s prognostic markers, such as FISH and immunoglobulin heavy chain variable region (IGHV)-mutation status, as well as the patient’s medical comorbidities and goals of care. For older, frailer patients with lower-risk CLL prognostic markers, NA monotherapy may remain a mainstay of CLL treatment for years to come. For younger, fitter patients and those with higher-risk CLL, such as del(17p) or unmutated IGHV, combination approaches may prove to be more valuable than NA monotherapy. Trials are currently evaluating the efficacy of several such combination approaches, including NA plus anti-CD20 monoclonal antibody, NA plus NA (with or without anti-CD20 monoclonal antibody), and NA plus CIT. Given the tremendous efficacy of the already approved NAs, as well as the promising data for next generation NAs, the development of well-tolerated, highly effective combination strategies with curative potential for patients with CLL has become a realistic goal.
Toward personalized treatment in Waldenström macroglobulinemia
Authors: Castillo Jorge J. , Treon Steven P. 
Published: April 2019

Abstract
Waldenström macroglobulinemia (WM) is a rare lymphoma with 1000 to 1500 new patients diagnosed per year in the United States. Patients with WM can experience prolonged survival times, which seem to have increased in the last decade, but relapse is inevitable. The identification of recurrent mutations in the MYD88 and CXCR4 genes has opened avenues of research to better understand and treat patients with WM. These developments are giving way to personalized treatment approaches for these patients, focusing on increasing depth and duration of response alongside lower toxicity rates. In the present document, we review the diagnostic differential, the clinical manifestations, and the pathological and genomic features of patients with WM. We also discuss the safety and efficacy data of alkylating agents, proteasome inhibitors, monoclonal antibodies, and Bruton tyrosine kinase inhibitors in patients with WM. Finally, we propose a genomically driven algorithm for the treatment of WM. The future of therapies for WM appears bright and hopeful, but we should be mindful of the cost-effectiveness and long-term toxicity of novel agents.
Advances in the diagnosis and treatment of Von Willebrand disease
Authors: Sharma Ruchika , Flood Veronica H. 
Published: April 2019

AbstractVon Willebrand disease (VWD) is the most common inherited bleeding disorder, yet diagnosis and management remain challenging. Development and use of bleeding assessment tools allows for improved stratification of which patients may require further assessment and which patients are most likely to require treatment of their VWD. New options for laboratory assessment of von Willebrand factor (VWF) activity include a new platelet-binding assay, the VWF:GPIbM, which is subject to less variability than the ristocetin cofactor activity assay, and collagen-binding assays that provide insight into a different function of VWF. Genetic testing may be helpful in some cases where a type 2 VWD variant is suspected but is usually not helpful in type 1 VWD. Finally, treatment options for VWD are reviewed, including the use of recombinant VWF. Despite these advances, still more work is required to improve diagnosis, treatment, and quality of life for affected patients.
Cardiovascular complications in patients with sickle cell disease
Authors: Gladwin Mark T. 
Published: April 2019

Abstract
Sickle cell disease (SCD) is an autosomal recessive disease in which homozygosity for a single point mutation in the gene encoding the β-globin chain produces hemoglobin S molecules that polymerize within the erythrocyte during deoxygenation; the result is sustained hemolytic anemia and vaso-occlusive events. As patients live to adulthood, the chronic impact of sustained hemolytic anemia and episodic vaso-occlusive episodes leads to progressive end-organ complications. This scenario culminates in the development of 1 or more major cardiovascular complications of SCD for which there are no approved or consensus therapies. These complications include elevated pulmonary artery systolic pressure, pulmonary hypertension, left ventricular diastolic heart disease, dysrhythmia, sudden death, and chronic kidney disease with associated proteinuria, microalbuminuria, and hemoglobinuria. In patients with advancing age, cardiopulmonary organ dysfunction and chronic kidney injury have significant effects on morbidity and premature mortality. Over the last 15 years, a number of tests have been validated in multiple replicate cohort studies that identify patients with SCD at the highest risk of experiencing pulmonary and systemic vasculopathy and death, providing for screening strategies tied to targeted, more aggressive diagnostic and therapeutic interventions.
Management of multiple myeloma in the newly diagnosed patient
Authors: Mateos María-Victoria , San Miguel Jesús F. 
Published: April 2019

AbstractMultiple myeloma is the second most frequent hematological disease. The introduction of melphalan as high-dose therapy followed by autologous hematopoietic cell transplantation (HDT/ASCT) for young patients and the availability of novel agents for young and elderly patients with multiple myeloma have dramatically changed the perspective of treatment. However, further research is necessary if we want definitively to cure the disease. Treatment goals for transplant-eligible and non–transplant-eligible patients should be to prolong survival by achieving the best possible response while ensuring quality of life. For young patients, HDT-ASCT is a standard of care for treatment, and its efficacy has been enhanced and challenged by the new drugs. For elderly patients, treatment options were once limited to alkylators, but new upfront treatment combinations based on novel agents (proteasome inhibitors and immunomodulatory drugs) combined or not with alkylators have significantly improved outcomes. Extended treatment of young and elderly patients improves the quality and duration of clinical responses; however, the optimal scheme, appropriate doses, and duration of long-term therapy have not yet been fully determined. This review summarizes progress in the treatment of patients with newly diagnosed multiple myeloma, addressing critical questions such as the optimal induction, early vs late ASCT, consolidation and/or maintenance for young patients, and how we can choose the best treatment option for non–transplant-eligible patients.
The role of targeted therapy in the management of patients with AML
Authors: Perl Alexander E. 
Published: April 2019

AbstractDrug therapy for acute myeloid leukemia (AML) is finally undergoing major changes in 2017. This is due to the US Food and Drug Administration’s approval of several new, targeted agents (midostaurin, enasidenib, and gemtuzumab ozogamicin). Paired with the recent approval of a novel liposomal formulation of daunorubicin/cytarabine (CPX-351/Vyxeos), the standard of care is changing rapidly in AML for subgroups. This review will focus on currently approved agents and promising novel agents in development and will highlight controversial areas in targeted treatment.
Responsiveness of Patient-Reported Outcome Measurement Information System (PROMIS) pain domains and disease-specific patient-reported outcome measures in children and adults with sickle cell disease
Authors: Curtis Susanna , Brandow Amanda M. 
Published: April 2019

AbstractCase 1: A 33-year-old man with hemoglobin SS (homozygous hemoglobin S) disease presents for his regular clinic visit. He had 6 hospital admissions for pain over the past year. He also has avascular necrosis of the right hip. He takes daily hydroxyurea with hematologic changes indicative of compliance. He also takes morphine sustained release twice daily and morphine immediate release every 6 hours as needed for pain. He feels that more optimal pain control at home would help him reduce his number of hospital admissions in the upcoming year and improve his daily functioning at home. His hematologist decides to use Patient-Reported Outcome Measurement Information System (PROMIS) and Adult Sickle Cell Quality of Life Measurement Information System (ASCQ-ME) to follow changes in the patient’s pain. Case 2: An 11-year-old girl with hemoglobin SS disease presents with her mother for her regular clinic visit. She had 2 admissions for pain over the past year. Her mother is concerned because she has been participating less in activities she previously enjoyed and missing classes to go to the school nurse because of pain. She is currently taking hydroxyurea and uses ibuprofen for pain. Her doctor prescribes morphine for home use but wants a way to measure if it is effective in improving her pain. Thus, her physician decides to use PROMIS and the Pediatric Quality of Life Inventory SCD (PedsQL SCD) module to determine the effectiveness of her pain control.
Using pharmacokinetics to individualize hemophilia therapy
Authors: Iorio Alfonso 
Published: April 2019

AbstractPrevention and treatment of bleeding in hemophilia requires that plasma clotting factor activity of the replaced factor exceeds a defined target level. Most clinical decisions in hemophilia are based on implicit or explicit application of pharmacokinetic measures. The large interindividual variability in pharmacokinetics of factor concentrates suggests that relying on the average pharmacokinetic characteristics of factor concentrates would not allow optimizing the treatment of individual patients; for example, adjusting the frequency of infusions and targeting a specific clotting factor activity level on a case-by-case basis. However, individual pharmacokinetic profiles are seldom assessed as part of routine clinical care. Population pharmacokinetics provide options for precise and convenient characterization of pharmacokinetics characteristics of factor concentrates, simplified individual pharmacokinetic profiling, and individualized dosing. Population pharmacokinetics allow for the incorporation of determinants of interpatient variability and reduces the need for extensive postinfusion plasma sampling. Barriers to the implementation of population pharmacokinetics are the need for concentrate-specific pharmacokinetic models, Bayesian calculation power, and specific expertise for production, validation, and appraisal of forecasted estimates. Population pharmacokinetics provide an important theoretical and practical contribution to tailoring the treatment of hemophilia. The need remains for prospective exploration of the clinical impact of tailoring hemophilia treatment based on individual pharmacokinetics, and for the systematic validation of existing software solutions and concentrate-specific models.
Anticoagulation with VADs and ECMO: walking the tightrope
Authors: Raffini Leslie 
Published: April 2019

Abstract
The evolution of devices for mechanical circulatory support (MCS), including ventricular assist devices (VADs) for patients with heart failure and extracorporeal membrane oxygenation (ECMO) for patients with acute cardiac or respiratory failure, has improved survival for subsets of critically ill children and adults. The devices are intricate and complex, allowing blood to bypass the heart or lungs (or both). As blood flows through these artificial devices, normal hemostasis is disrupted, coagulation is promoted, and in the absence of anticoagulation, a thrombus may form in the device, resulting in device failure or embolic stroke. Therefore, anticoagulation is necessary to prevent thrombus formation and maintain device function. However, patients on MCS also have very high bleeding rates. Titrating anticoagulation to prevent hemorrhagic complications and thrombotic events can be a challenge, and hematologists may be consulted in complex cases. Substantial variability remains in the approach to anticoagulant and antiplatelet therapy for patients on MCS, largely because of the lack of high-quality data. Improvements in the design and manufacture of these devices, as well as in the individualized titration of antithrombotic intensity, are expected to enhance outcomes. Several factors pertaining to both the device and the patient (adult and children) should be considered when attempting to optimize this delicate balance.
Inherited bone marrow failure syndromes: considerations pre- and posttransplant
Authors: Alter Blanche P. 
Published: April 2019

AbstractPatients with inherited bone marrow failure syndromes are usually identified when they develop hematologic complications such as severe bone marrow failure, myelodysplastic syndrome, or acute myeloid leukemia. They often have specific birth defects or other physical abnormalities that suggest a syndrome, and sequencing of specific genes or next-generation sequencing can determine or confirm the particular syndrome. The 4 most frequent syndromes are Fanconi anemia, dyskeratosis congenita, Diamond Blackfan anemia, and Shwachman Diamond syndrome. This review discusses the major complications that develop as the patients with these syndromes age, as well as additional late effects following hematopoietic stem cell transplantation. The most common complications are iron overload in transfused patients and syndrome-specific malignancies in untransplanted patients, which may occur earlier and with higher risks in those who have received transplants.