bluuebunny/crossref_metadata_2025_split huggingface dataset:
BCR pathway inhibition as therapy for chronic lymphocytic leukemia and lymphoplasmacytic lymphoma
Authors: Wiestner Adrian 
Published: November 2014

Abstract
Chronic lymphocytic leukemia (CLL) and lymphoplasmacytic lymphoma (LPL) are malignancies of mature B cells. In LPL, mutations of the adaptor protein MYD88 (L265P) in the Toll-like receptor pathway have been recognized recently as being a hallmark of the disease and indicate a dependence of the tumor on this pathway. In CLL, functional studies have implicated BCR activation in the tissue microenvironment as a pivotal pathway in the pathogenesis. Bruton's tyrosine kinase (BTK) and the PI3Kδ isoform are essential for BCR signaling and also seem to be required for signal transduction in LPL cells, even if the role of BCR signaling in this disease remains less well defined. Ibrutinib, a covalent inhibitor of BTK approved by the Food and Drug Administration as a second-line treatment for CLL, and idelalisib, a selective inhibitor of PI3Kδ, achieve excellent clinical responses in both diseases irrespective of classic markers indicating high-risk disease. Several additional inhibitors targeting BTK and PI3Kδ, as well as the spleen tyrosine kinase, have entered clinical trials. This review discusses the biologic basis for kinase inhibitors as targeted therapy for CLL and LPL and summarizes the clinical experience with these agents.
Indolent lymphoma: follicular lymphoma and the microenvironment—insights from the microscope
Authors: Harris Nancy Lee 
Published: November 2014

AbstractFollicular lymphomas (FLs) are neoplasms of germinal center (GC) B cells, which retain many of the morphologic, immunophenotypic, genetic, and functional features of normal GC B cells. Both normal GCs and neoplastic follicles of FL also contain non-neoplastic cells (microenvironment) that influence and are influenced by the GC and FL B cells and are likely important for tumor cell survival. Many insights into the nature of the GC/FL microenvironment have come from morphologic and immunophenotypic analysis, both before and after the discoveries from gene expression profiling. This chapter reviews what we have learned from the microscope and highlights the pitfalls involved in trying to enumerate cells in the microenvironment for clinical prognostication.
Indolent lymphoma: follicular lymphoma and the microenvironment—insights from gene expression profiling
Authors: Rimsza Lisa M. , Jaramillo Melba C. 
Published: November 2014

Abstract
As shown with gene expression profiling (GEP), the development and progression of follicular lymphoma (FL) involves complex interactions between neoplastic B cells and the surrounding microenvironment. GEP further reveals that the tumor microenvironment may predict survival in patients with FL and influence the response to therapy and the risk of transformation. Here, we briefly review GEP technology and summarize the role of the tumor microenvironment in FL diagnosis, prognosis, and transformation. Genes expressed by infiltrating T cells and macrophages appear to be the most important predictors of survival, clinical behavior, and outcome. These findings provide a basis for future studies into the pathogenesis and pathophysiology of FL and may ultimately provide guidance in the choice of therapy and the identification of potential therapeutic targets.
Therapeutic targeting of microenvironment in follicular lymphoma
Authors: Nowakowski Grzegorz S. , Ansell Stephen M. 
Published: November 2014

AbstractImmune and nonimmune microenvironmental factors play a critical role in the progression, transformation, and resistance to therapy in follicular lymphoma (FL). A recent increase in our understanding of the role of microenvironment in FL biology has led to the development of novel therapeutic strategies targeting the nonimmune and immune microenvironment. These include immunomodulatory drugs, immune checkpoint inhibitors, immnunoconjugates, and small-molecule inhibitors with an impact on the microenvironment in addition to direct antitumor activity. These agents are now at different stages of clinical development, ranging from early clinical trials in relapsed disease to phase 3 studies in the upfront setting, including combinations with other agents such as monoclonal antibodies and chemotherapy. It is important to recognize that, although the current upfront therapy of FL is associated with favorable outcomes in the majority of patients, a significant proportion experience early disease progression and develop treatment resistance and transformation to aggressive lymphoma. Although the development of “chemo-free” combinations using drugs targeting the microenvironment offers a promising approach to minimize toxicity, the identification of patients at risk of relapse and the use of biomarkers allowing the personalization of therapy will likely play a major role in the development of maintenance strategies. Against this landscape of currently available therapy options, this chapter discusses the clinical status of therapies targeting the microenvironment in FL.
The genomic landscape of acute lymphoblastic leukemia in children and young adults
Authors: Mullighan Charles G. 
Published: November 2014

Abstract
Our understanding of the genetic basis of childhood acute lymphoblastic leukemia (ALL) has been greatly advanced by genomic profiling and sequencing studies. These efforts have characterized the genetic basis of recently described and poorly understood subtypes of ALL, including early T-cell precursor ALL, Philadelphia chromosome–like (Ph-like) ALL, and ALL with intrachromosomal amplification of chromosome 21, and have identified several rational therapeutic targets in high-risk ALL, notably ABL1-class and JAK-STAT inhibitors in Ph–like ALL. Deep sequencing studies are also refining our understanding of the genetic basis of clonal heterogeneity and relapse. These studies have elucidated the nature of clonal evolution during disease progression and identified genetic changes that confer resistance to specific therapeutic agents, including CREBBP and NT5C2. Genomic profiling has also identified common and rare inherited genetic variants that influence the risk of developing leukemia. These efforts are now being extended to ALL in adolescents and adults with the goal of fully defining the genetic landscape of ALL to further improve treatment outcomes in high-risk populations.
Clinically defining and managing high-risk pediatric patients with acute lymphoblastic leukemia
Authors: Alexander Sarah 
Published: November 2014

Abstract
For children with acute lymphoblastic leukemia, the identification of those at higher risk of disease recurrence and modifying therapy based on this risk is a critical component to the provision of optimal care. The specific definitions of high-risk ALL vary across cooperative groups, but the themes are consistent, being largely based on leukemia biology and disease response. Intensification of conventional chemotherapy for those with high-risk disease has led to improved outcomes. It is anticipated that the development of rational targeted therapy for specific biologically unique subsets of children with leukemia will contribute to ongoing progress in improving the outcomes for children with acute lymphoblastic anemia.
Guidelines for quantifying iron overload
Authors: Wood John C. 
Published: November 2014

Abstract
Both primary and secondary iron overload are increasingly prevalent in the United States because of immigration from the Far East, increasing transfusion therapy in sickle cell disease, and improved survivorship of hematologic malignancies. This chapter describes the use of historical data, serological measures, and MRI to estimate somatic iron burden. Before chelation therapy, transfusional volume is an accurate method for estimating liver iron burden, whereas transferrin saturation reflects the risk of extrahepatic iron deposition. In chronically transfused patients, trends in serum ferritin are helpful, inexpensive guides to relative changes in somatic iron stores. However, intersubject variability is quite high and ferritin values may change disparately from trends in total body iron load over periods of several years. Liver biopsy was once used to anchor trends in serum ferritin, but it is invasive and plagued by sampling variability. As a result, we recommend annual liver iron concentration measurements by MRI for all patients on chronic transfusion therapy. Furthermore, it is important to measure cardiac T2* by MRI every 6-24 months depending on the clinical risk of cardiac iron deposition. Recent validation data for pancreas and pituitary iron assessments are also presented, but further confirmatory data are suggested before these techniques can be recommended for routine clinical use.
Prognostic significance of early molecular response in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors
Authors: Yeung David T. , Mauro Michael J. 
Published: November 2014

AbstractA 55-year-old man presented with splenomegaly (10 cm below left costal margin) and leucocytosis (145 × 109/L). Differential showed neutrophilia with increased basophils (2%), eosinophils (1.5%), and left shift including myeloblasts (3%). A diagnosis of chronic myeloid leukemia in chronic phase was established after marrow cytogenetics demonstrated the Philadelphia chromosome. Molecular studies showed a BCR-ABL1 qPCR result of 65% on the International Scale. Imatinib therapy at 400 mg daily was initiated due to patient preference, with achievement of complete hematological response after 4 weeks of therapy. BCR-ABL1 at 1 and 3 months after starting therapy was 37% and 13%, respectively (all reported on International Scale). Is this considered an adequate molecular response?
A practical approach to relapsed multiple myeloma
Authors: Mikhael Joseph R. 
Published: November 2014

Abstract
There has been tremendous progress made in multiple myeloma in the last decade, resulting in improved overall survival for all patients, including those with high-risk disease and those ineligible for transplantation. However, despite the addition of several novel agents, unprecedented response rates, and our ability to achieve complete remission in the majority of patients, the disease remains incurable in nearly all and will require repeated therapies. With many options available to the clinician, there is no simple or ideal sequence of treatments that has been established, so the choice of relapsed therapy is based on a series of factors that include response and tolerability of prior therapies, risk status, available novel agents, aggressiveness of relapse, renal function, performance status, cost, etc. This chapter provides practical guidance in selecting relapsed therapies structured through a series of 5 questions that can inform the decision. Specific emphasis is placed on the 2 most recent novel agents, carfilzomib and pomalidomide, but agents in development are also included.
How does JAK2V617F contribute to the pathogenesis of myeloproliferative neoplasms?
Authors: Chen Edwin , Mullally Ann 
Published: November 2014

AbstractA decade on from the discovery of the JAK2V617F mutation in the majority of patients with myeloproliferative neoplasms (MPNs), JAK2V617F is now firmly installed in the hematology curriculum of medical students and the diagnostic-testing algorithm of clinicians. Furthermore, the oral JAK1/JAK2 inhibitor ruxolitinib, rationally designed to target activated JAK2 signaling in MPN, has been approved by the Food and Drug Administration (FDA) of the United States for the past 3 years for the treatment of intermediate- and advanced-phase myelofibrosis. Notwithstanding this, JAK2V617F continues to stimulate the MPN research community and novel insights into understanding the mechanisms by which JAK2V617F contributes to the pathogenesis of MPN are continually emerging. In this chapter, we focus on recent advances in 4 main areas: (1) the molecular processes coopted by JAK2V617F to induce MPN, (2) the role that JAK2V617F plays in phenotypic diversity in MPN, (3) the functional impact of JAK2V617F on hematopoietic stem cells, and (4) therapeutic strategies to target JAK2V617F. Although great strides have been made, significant deficits still exist in our understanding of the precise mechanisms by which JAK2V617F-mutant hematopoietic stem cells emerge and persist to engender clonal hematopoiesis in MPN and in developing strategies to preferentially target the JAK2V617F-mutant clone therapeutically. Critically, although myelofibrosis remains arguably the greatest clinical challenge in JAK2V617F-mediated MPN, the current understanding of myelofibrosis-specific disease biology remains quite rudimentary. Therefore, many important biological questions pertaining to JAK2V617F will continue to engage and challenge the MPN research community in the coming decade.
Central venous catheter–related thrombosis
Authors: Geerts William 
Published: November 2014

Abstract
Thrombotic complications associated with the use of central venous catheters (CVCs) are common and lead to distressing patient symptoms, catheter dysfunction, increased risk of infections, long-term central venous stenosis, and considerable costs of care. Risk factors for catheter-related thrombosis include use of larger, multilumen, and peripherally inserted catheters in patients with cancer receiving chemotherapy. Symptomatic catheter-related thrombosis is treated with anticoagulation, generally without removing the catheter. The intensity and duration of anticoagulation depend on the extent of thrombosis, risk of bleeding, and need for continued use of a CVC. To date, the clinical benefit of prophylactic doses of anticoagulant has been disappointing and these agents are not used routinely for this purpose. This chapter focuses on recent evidence, remaining controversies, and practical approaches to reducing the burden of thrombosis associated with CVCs.
Genetic basis of congenital platelet disorders
Authors: Hinckley Jesse , Di Paola Jorge 
Published: November 2014

Abstract
Over the past 4 decades, a better understanding of the genetic origins of inherited platelet disorders has illuminated avenues of investigation in megakaryopoiesis and has identified targets of pharmacologic intervention. Many of these discoveries have been translated into clinical medicine. The success of inherited platelet disorder research is underpinned by broader advances in methodology through the biochemical and molecular revolution of the 20th and 21st centuries, respectively. Recently, modern genomics techniques have affected platelet and platelet disorders research, allowing for the discovery of several genes involved in platelet production and function and for a deeper understanding of the RNA and miRNA networks that govern platelet function. In this short review, we focus on recent developments in the genetic elucidation of several disorders of platelet number and in the molecular architecture that determines the “genetic makeup” of a platelet in health and disease.
Pregnancy and venous thromboembolism: ‘TIPPS’ for risk stratification
Authors: Rodger Marc 
Published: November 2014

AbstractPregnancy-associated venous thromboembolism (VTE) is a leading cause of maternal mortality, but is relatively uncommon. It is clear that the antepartum and postpartum periods have different magnitudes of risk and distinct risk factors for VTE and therefore must be considered separately. Absolute daily risks of VTE must be understood and explored when deciding to prescribe antepartum or postpartum thromboprophylaxis and must also be balanced against the downsides of prophylaxis. When the risks for VTE and bleeding are both low, other burdens of thromboprophylaxis must be weighed in and a decision made after an individualized patient values- and patient preferences–based discussion. Risk stratification is essential to ensure that the practicing clinician strikes the right balance.
Anticoagulation in pregnancy complications
Authors: Middeldorp Saskia 
Published: November 2014

AbstractWomen with acquired and inherited thrombophilia are thought to be at increased risk for pregnancy complications, including recurrent pregnancy loss and, depending on the type of thrombophilia, severe preeclampsia. This review discusses the associations between the types of thrombophilia and types of complications, as well as the currently available clinical trial evidence regarding the use of aspirin and heparin to prevent these pregnancy complications. In women with antiphospholipid syndrome, guidelines recommend prescribing aspirin and heparin to women with recurrent miscarriage. The same regimen is suggested for late pregnancy complications by some, but not all, experts. Aspirin or low-molecular-weight heparin to improve pregnancy outcome in women with unexplained recurrent miscarriage has no benefit and should not be prescribed. Whether anticoagulant therapy prevents recurrent miscarriage in women with inherited thrombophilia or in women with severe pregnancy complications remains controversial because of inconsistent results from trials. Aspirin modestly decreases the risk of severe preeclampsia in women at high risk.
Platelets: more than a sack of glue
Authors: Weyrich Andrew S. 
Published: November 2014

AbstractPlatelets are primary effector cells in hemostasis. Emerging evidence over the last decade, however, demonstrates that platelets also have critical roles in immunity and inflammation. These nontraditional functions of platelets influence the development, progression, and evolution of numerous diseases, including arthritis, cancer, cardiovascular disease, and infectious syndromes. This chapters reviews recently discovered attributes of platelets that contribute to human disease, paying particular attention to the inflammatory activities of this anucleate cytoplast.
Breakthrough: new guidance for silent cerebral ischemia and infarction in sickle cell disease
Authors: Quinn Charles T. 
Published: November 2014

Abstract
Silent cerebral infarction (SCI) is a highly prevalent and morbid condition in sickle cell disease (SCD). SCI can occur beginning in the first year of life and becomes more common with increasing age. Potentially modifiable risk factors for SCI include anemia and blood pressure. Headache does not appear to be associated with SCI, so neurologically normal children with headache do not necessarily warrant screening MRI for SCI. SCI does affect cognition, but biological determinants of cognition are not more important than socioeconomic factors. The recent identification of acute silent cerebral ischemic events indicates that the total burden of ischemic injury to the brain in SCD is far greater than previously realized. Acute anemic events appear to increase the risk of acute silent cerebral ischemic events and SCI dramatically. The medical management of SCI is not yet defined, but documentation of the presence of SCI may qualify affected individuals for special resources because comprehensive interventions are needed to optimize patients' academic and vocational outcomes.
Epigenetic targeting and personalized approaches for AML
Authors: Roboz Gail J. 
Published: November 2014

Abstract
Acute myeloid leukemia (AML) is a genetically heterogeneous clonal hematopoietic stem cell disorder and the majority of patients with AML die from their disease. The treatment paradigms for AML were developed decades ago and, although there have been improvements in the outcomes of selected younger patients and those with specific cytogenetic and molecular genetic characteristics, the overall survival for older patients remains dismal. Over the last few years, next-generation sequencing technologies have identified recurrent mutations in genes encoding proteins involved in the epigenetic regulation of transcription in most patients with AML. This discovery has led to new insights into the role of the epigenome in AML and opens the possibility of epigenetically targeted therapies. This chapter describes how epigenetic dysregulation plays a role in AML and highlights current and future treatment strategies that attempt to exploit epigenetic targets.
Leukocytapheresis for the treatment of hyperleukocytosis secondary to acute leukemia
Authors: Aqui Nicole , O'Doherty Una 
Published: November 2014

Abstract
Patients presenting with new or recurrent acute leukemia, particularly of the myeloid lineage, with WBC counts exceeding 100 × 109/L are often considered for leukocytapheresis, especially if they are experiencing symptoms of leukostasis. These symptoms are thought to occur because of blast aggregates and WBC thrombi in the circulation, which reduce blood flow. Leukostasis may cause various complications, including hyperviscosity syndrome, vascular occlusion resulting in intracranial hemorrhages and respiratory failure, and perivascular leukemic infiltrates. Leukostasis occurs more commonly with a high WBC count and with leukemias of monocytoid lineage such as acute myelomonocytic leukemia, which is a reflection of the nature of the leukemic blasts. Leukocytapheresis is used in an effort to quickly decrease a patient's circulating blast count, which can both prevent the development of leukostasis and provide symptomatic relief of leukostasis. However, the impact of leukocytapheresis on early- and long-term mortality is controversial, with several studies producing conflicting results. In this chapter, the pathophysiology of leukostasis, performance of leukocytapheresis, and efficacy of this treatment are reviewed.
Bleeding complications of targeted oral anticoagulants: what is the risk?
Authors: Levine Michael , Goldstein Joshua N. 
Published: November 2014

Abstract
The vitamin K antagonists (VKAs) are a widely used class of agent to prevent thromboembolism. In recent years, numerous alternatives to VKAs have been developed, the target-specific oral anticoagulants (TSOACs), which are available in clinical practice. Currently available agents target thrombin and factor Xa. The most significant side effect of these agents, as with VKAs, is the development of bleeding complications. In this review, the risks of major bleeding complications with the TSOACs will be discussed. Data from meta-analyses, randomized controlled trials, and observational studies will be used to highlight bleeding complications associated with TSOACs and warfarin. We highlight the most common causes of major bleeding, GI and intracranial hemorrhage.
Future prospects for contact factors as therapeutic targets
Authors: Gailani David 
Published: November 2014

Abstract
Anticoagulants currently used in clinical practice to treat or prevent thromboembolic disease are effective, but place patients at increased risk for serious bleeding because they interfere with plasma enzymes (thrombin and factor Xa) that are essential for hemostasis. In the past 10 years, work with genetically altered mice and studies in baboons and rabbits have demonstrated that the plasma contact proteases factor XI, factor XII, and prekallikrein contribute to the formation of occlusive thrombi despite having limited roles in hemostasis. In the case of factor XI, epidemiologic data from human populations indicate that elevated levels of this protein increase risk for stroke and venous thromboembolism and may also influence risk for myocardial infarction. These findings suggest that inhibiting contact activation may produce an antithrombotic effect without significantly compromising hemostasis. This chapter reviews strategies that are being developed for therapeutic targeting of factor XI and factor XII and their performances in preclinical and early human trials.