bluuebunny/crossref_metadata_2025_split huggingface dataset:
Harnessing the power of the immune system in non-Hodgkin lymphoma: immunomodulators, checkpoint inhibitors, and beyond
Authors: Ansell Stephen M. 
Published: April 2019

Abstract
Non-Hodgkin lymphoma is a malignancy of B lymphocytes that typically infiltrate sites of disease, including the lymph nodes, spleen, and bone marrow. Beyond the presence of malignant cells, many immune cells are also present within the tumor microenvironment. Although these immune cells have the potential to regulate the growth of malignant B cells, intratumoral immune cells are unable to eradicate lymphoma cells and most patients with lymphoma have clinical evidence of disease progression. Recent data have identified some of the mechanisms that account for the suppressed antitumor immune response and have created opportunities for treatment to overcome the deficiencies. Two general categories of immunological therapies are available. The first approach is to use agents that prevent inhibitory signals via immune checkpoint receptors that downregulate immune cell function. Blockade of suppressive programmed cell death 1 (PD-1) or CTLA-4 signaling has resulted in significant clinical activity by allowing intratumoral T cells to remain activated and target malignant cells. A second approach is to additionally activate T cells that are suboptimally active or suppressed, by providing signals through costimulatory molecules including CD27 or CD40 or by adding immunostimulatory cytokines. There has been significant heterogeneity in the responses to these treatment approaches. Clinical responses are seen in many diseases, but the most promising responses have been with PD-1 blockade in Hodgkin lymphoma. In other lymphomas, responses are seen but only in a subset of patients. Further research is needed to identify the mechanisms that account for response and to identify patients most likely to benefit from immune modulation.
JAK2 (and other genes) be nimble with MPN diagnosis, prognosis, and therapy
Authors: Ciboddo Michele , Mullally Ann 
Published: April 2019

Abstract
Now that the spectrum of somatic mutations that initiate, propagate, and drive the progression of myeloproliferative neoplasms (MPNs) has largely been defined, recent efforts have focused on integrating this information into clinical decision making. In this regard, the greatest progress has been made in myelofibrosis, in which high-molecular-risk mutations have been identified and incorporated into prognostic models to help guide treatment decisions. In this chapter, we focus on advances in 4 main areas: (1) What are the MPN phenotypic driver mutations? (2) What constitutes high molecular risk in MPN (focusing on ASXL1)? (3) How do we risk-stratify patients with MPN? And (4) What is the significance of molecular genetics for MPN treatment? Although substantial progress has been made, we still have an incomplete understanding of the molecular basis for phenotypic diversity in MPN, and few rationally designed therapeutic approaches to target high-risk mutations are available. Ongoing research efforts in these areas are critical to understanding the biological consequences of genetic heterogeneity in MPN and to improving outcomes for patients.
Long-term complications in adolescent and young adult leukemia survivors
Authors: Baker K. Scott , Syrjala Karen L. 
Published: April 2019

Abstract
Adolescents and young adults (AYAs) with cancer, defined by the National Cancer Institute as having been diagnosed between the ages of 15 and 39 years old, have not benefited from the same improvements in quality of outcomes and survival that have been seen for individuals diagnosed in childhood or as older adults. Although is leukemia composed of a diverse group of diagnoses, leukemia AYA survivors share unique vulnerabilities with other AYA diagnostic groups. They will spend the majority of their lives as survivors, with clear evidence of adverse medical conditions, health care requirements, and social and psychological needs that differ not only from their peers but also, from the needs of other cancer survivor populations. Furthermore, they share a developmental stage of life in which careers, finances, and family concerns are uniquely impacted by the cancer diagnosis and treatment. Leukemia in AYAs typically presents with higher-risk biologic features, and treatment requires multiagent chemotherapy, including alkylating agents, anthracyclines, high-dose steroids, frequently intrathecal chemotherapy, and sometimes, cranial radiation. Thus, AYAs have significant risks for long-term complications, subsequent malignancies, and accelerated development of usual age-related comorbid conditions, such as cardiovascular disease and dyslipidemias. AYAs require specialized health care monitoring, surveillance for late effects, and periodic evaluation of psychosocial, health behavior, and life goal outcomes.
We do still transplant CML, don’t we?
Authors: Craddock Charles F. 
Published: April 2019

Abstract
The remarkable clinical activity of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) has transformed patient outcome. Consequently, allogeneic stem cell transplantation (allo-SCT) is no longer the only treatment modality with the ability to deliver long-term survival. In contrast to the central position it held in the treatment algorithm 20 years ago, allografting is now largely reserved for patients with either chronic-phase disease resistant to TKI therapy or advanced-phase disease. Over the same period, progress in transplant technology, principally the introduction of reduced intensity conditioning regimens coupled with increased donor availability, has extended transplant options in patients with CML whose outcome can be predicted to be poor if they are treated with TKIs alone. Consequently, transplantation is still a vitally important, potentially curative therapeutic modality in selected patients with either chronic- or advanced-phase CML. The major causes of transplant failure in patients allografted for CML are transplant toxicity and disease relapse. A greater understanding of the distinct contributions made by various factors such as patient fitness, patient-donor HLA disparity, conditioning regimen intensity, and transplant toxicity increasingly permits personalized transplant decision making. At the same time, advances in the design of conditioning regimens coupled with the use of adjunctive posttransplant cellular and pharmacologic therapies provide opportunities for reducing the risk of disease relapse. The role of SCT in the management of CML will grow in the future because of an increase in disease prevalence and because of continued improvements in transplant outcome.
Where to start? Upfront therapy for follicular lymphoma in 2018
Authors: Leonard John P. , Nastoupil Loretta J. , Flowers Christopher R. 
Published: April 2019

Abstract
The initial approach to the management of follicular lymphoma (FL) is challenging for patients and physicians. Most FL patients present with minimal symptoms; given the lack of a survival benefit to early treatment in this population, a period of observation without therapy is often appropriate. Once there is disease progression beyond low-tumor-burden criteria or symptoms prompting intervention, patients may be considered for an array of potential treatment options. These range from single-agent rituximab (anti-CD20) to various forms of chemoimmunotherapy, including rituximab or the newer anti-CD20 monoclonal antibody obinutuzumab. Unfortunately, prognostic and other clinical factors are of limited value in guiding optimal selection of therapy. Once patients complete initial treatment and achieve a complete or a partial remission, the next decision relates to the pros and cons of maintenance anti-CD20 therapy. Maintenance antibody administration can improve progression-free, but not overall, survival; hence, patient preferences typically drive this decision. Monitoring after remission is achieved should generally be guided by symptoms, physical examination, and laboratory findings, with routine surveillance imaging discouraged in the absence of new clinical issues. Given the wide range of options available and the importance of optimizing quality of life in this chronic health condition, education and shared decision making are pillars in the upfront management of FL to help patients achieve the best possible outcomes.
Biology-driven developments in the therapy of acute graft-versus-host disease
Authors: Zeiser Robert 
Published: April 2019

Abstract
Allogeneic hematopoietic cell transplantation is a potentially curative treatment of different hematological malignancies. A major life-threatening complication is acute graft-versus-host disease (GVHD), in particular when the disease becomes steroid refractory. Based on the detection of pathogenic cytokines, chemokines, and T-cell subsets in individuals developing GVHD or experimental GVHD models, different therapeutic strategies have been developed. A potential cause why targeting individual receptors can lack efficacy could be that multiple cytokines, danger signals, and chemokine that have redundant functions are released during GVHD. To overcome this redundancy, novel strategies that do not target individual surface molecules like chemokine receptors, integrins, and cytokine receptors, but instead inhibit signaling pathways downstream of these molecules, have been tested in preclinical GVHD models and are currently being tested in clinical GVHD trials. Another important development is tissue regenerative approaches that promote healing of GVHD-related tissue damage as well as strategies that rely on microbiota modifications. These approaches are promising because they act very differently from conventional immunosuppression, instead aiming at reinstalling tissue homeostasis and microbiome diversity. This review discusses major novel developments in GVHD therapy that are based on a better understanding of GVHD biology, the repurposing of novel kinase inhibitors, microbiome modification strategies, and tissue-regenerative approaches.
Hypereosinophilic syndrome: approach to treatment in the era of precision medicine
Authors: Klion Amy 
Published: April 2019

Abstract
Hypereosinophilic syndromes (HESs) are a heterogeneous group of rare disorders characterized by peripheral eosinophilia and eosinophilic end organ complications. Conventional therapies, including glucocorticoids and cytotoxic and immunomodulatory agents, have variable efficacy and significant toxicity. Although the recent development of agents that target eosinophils, including tyrosine kinase inhibitors and monoclonal antibodies, provides the possibility of more effective, less toxic approaches to treatment of HES, there are little available data to guide their use in these conditions. In the following review, the controversies regarding the definition and classification of HES will be discussed, and a pragmatic approach to treatment based on clinically defined HES variants will be presented. An illustrative case will be used to highlight the complexities of treatment selection in HES patients.
Optimizing quality care for the oral vitamin K antagonists (VKAs)
Authors: Pengo Vittorio , Denas Gentian 
Published: April 2019

Abstract
Vitamin K antagonists (VKAs) have been the only oral anticoagulants for decades. The management of anticoagulant therapy with VKA is challenging because of the intricate pharmacological properties of these agents. The success of VKA therapy depends on the quality of treatment that is ensured through continuing comprehensive communication and education. The educational program should address important issues of the VKA therapy such as beginning of treatment, pharmacological, dietary, and drug–drug interactions, as well as treatment temporary suspension during surgical interventions or invasive maneuvers. In addition, the initial and continuing patient education is of imperative importance. A major role in the educational process may be addressed by patient associations. The quality of treatment is better reached if patients are followed in anticoagulation clinics. Moreover, a federation of anticoagulation clinics may improve patient care through regular meetings to update knowledge on VKA treatment. Learning objectives of this paper is to allow readers to correctly approach patients starting VKA treatment, recognize possible pitfalls of treatment, and provide adequate solutions.
Potential new approaches to the management of the Hb Bart’s hydrops fetalis syndrome: the most severe form of α-thalassemia
Authors: King Andrew J. , Higgs Douglas R. 
Published: April 2019

Abstract
The α-thalassemia trait, associated with deletions removing both α-globin genes from 1 chromosome (genotype ζ αα/ζ--), is common throughout Southeast Asia. Consequently, many pregnancies in couples of Southeast Asian origin carry a 1 in 4 risk of producing a fetus inheriting no functional α-globin genes (ζ--/ζ--), leading to hemoglobin (Hb) Bart’s hydrops fetalis syndrome (BHFS). Expression of the embryonic α-globin genes (ζ-globin) is normally limited to the early stages of primitive erythropoiesis, and so when the ζ-globin genes are silenced, at ∼6 weeks of gestation, there should be no α-like globin chains to pair with the fetal γ-globin chains of Hb, which consequently form nonfunctional tetramers (γ4) known as Hb Bart’s. When deletions leave the ζ-globin gene intact, a low level of ζ-globin gene expression continues in definitive erythroid cells, producing small amounts of Hb Portland (ζ2γ2), a functional form of Hb that allows the fetus to survive up to the second or third trimester. Untreated, all affected individuals die at these stages of development. Prevention is therefore of paramount importance. With improvements in early diagnosis, intrauterine transfusion, and advanced perinatal care, there are now a small number of individuals with BHFS who have survived, with variable outcomes. A deeper understanding of the mechanism underlying the switch from ζ- to α-globin expression could enable persistence or reactivation of embryonic globin synthesis in definitive cells, thereby providing new therapeutic options for such patients.
Balancing exercise risk and benefits: lessons learned from sickle cell trait and sickle cell anemia
Authors: Liem Robert I. 
Published: April 2019

AbstractDevelopment of exercise guidelines for individuals with sickle cell trait (SCT) and sickle cell anemia (SCA) is hampered by the need to weigh the benefits against risks of exercise in these populations. In SCT, concern for exercise collapse associated with sickle cell trait has resulted in controversial screening of student athletes for SCT. In SCA, there exists unsubstantiated concerns that high-intensity exercise may result in pain and other complications. In both, finding the “right dose” of exercise remains a challenge for patients and their providers. Despite assumptions that factors predisposing to adverse events from high-intensity exercise overlap in SCT and SCA, the issues that frame our understanding of exercise-related harms in both are distinct. This review will compare issues that affect the risk-benefit balance of exercise in SCT and SCA through these key questions: (1) What is the evidence that high-intensity exercise is associated with harm? (2) What are the pathophysiologic mechanisms that could predispose to harm? (3) What are the preventive strategies that may reduce risk? and (4) Why do we need to consider the benefits of exercise in this debate? Addressing these knowledge gaps is essential for developing an evidence-based exercise prescription for these patient populations.
The current state of sickle cell trait: implications for reproductive and genetic counseling
Authors: Pecker Lydia H. , Naik Rakhi P. 
Published: April 2019

Abstract
Sickle cell trait (SCT) is unique among the carrier states that are identified during newborn screening. Unlike other heterozygous states for rare recessive diseases, SCT is exceedingly prevalent throughout regions of the world, making sickle cell disease one of the most common monogenetic diseases worldwide. Because of this high frequency, reproductive counseling is of paramount importance. In addition, unlike other carrier states, SCT seems to be a risk factor for several clinical complications, such as extreme exertional injury, chronic kidney disease, and venous thromboembolism. Increasing knowledge about these clinical outcomes can help inform genetic counseling recommendations. Expanding research and clinical efforts are needed to ensure that the promises of modern and precision medicine can be delivered to the millions of SCT carriers and their children.
An introduction to point-of-care testing in extracorporeal circulation and LVADs
Authors: Bercovitz Rachel Sara 
Published: April 2019

Abstract
There is a delicate balance between bleeding and clotting in patients on circuits such as ventricular assist devices or extracorporeal membrane oxygenation. Traditional coagulation tests, prothrombin time, activated partial thromboplastin time, and anti-factor Xa levels, are used to monitor patients on these devices. However, turnaround times and inability to assess global hemostasis, including platelets and fibrinogen have contributed to a recognition that faster, accurate, and more informative coagulation tests are needed. Activated clotting time is used to monitor heparin in patients on circuits and has the advantages of being a near-patient point-of-care test. However, its utility is limited to heparin monitoring. Viscoelastic tests (thromboelastometry and thromboelastography) are global, whole-blood coagulation tests, and whole-blood platelet aggregometry evaluates platelet function. Ideally, these tests can ensure that patients are within the therapeutic range of their antithrombotic medications, identify patients at risk for hemorrhagic or thrombotic complications, and guide management of acute bleeding complications. This ideal is currently hampered by a lack of studies that delineate clear ranges that are clinically relevant. Future research is needed to better understand the optimal use of point-of-care coagulation testing in patients on extracorporeal circuits and ventricular assist devices.
How do we diagnose immune thrombocytopenia in 2018?
Authors: Kelton John G. , Vrbensky John R. , Arnold Donald M. 
Published: April 2019

AbstractIn this report, we will review the various clinical and laboratory approaches to diagnosing immune thrombocytopenia (ITP), with a focus on its laboratory diagnosis. We will also summarize the results from a number of laboratories that have applied techniques to detect anti-platelet autoantibodies as diagnostic tests for ITP. Although there is considerable variability in methods among laboratories, there is general agreement that platelet autoantibody testing has a high specificity but low sensitivity. This suggests several possibilities: (1) the ideal test for ITP has yet to be developed, (2) current test methods need to be improved, or (3) ITP is the clinical expression of a variety of thrombocytopenic disorders with different underlying mechanisms. Even the clinical diagnosis of ITP is complex, and experienced clinicians do not always agree on whether a particular patient has ITP. Improvements in the diagnostic approach to ITP are necessary to improve the management of this disorder.
Treatment approach for the older, unfit patient with myeloma from diagnosis to relapse: perspectives of a European hematologist
Authors: Facon Thierry , Anderson Kenneth 
Published: April 2019

AbstractMrs. A. is a 73-year-old woman who has developed increasing fatigue and lower back pain over the past year. The pain limits her exercise tolerance such that she can now walk only 1 block. She is a retired schoolteacher who does volunteer efforts in her community but has limited her activities due to fatigue. Karnofsky performance status is 70%. She has a history of chronic hypertension treated with a diuretic, adult-onset diabetes mellitus treated with metformin, and hypothyroidism treated with levothyroxine. Initial evaluation reveals anemia, renal dysfunction, an elevated total protein, and an L2 compression fracture on lumbosacral radiographs. Results of initial and subsequent evaluation are shown below, and she is referred to a hematologist for further evaluation, which revealed the following: calcium 9.0 mg/dL, creatinine 3.2 mg/dL with estimated creatinine clearance using the Modification of Diet in Renal Disease equation of 15 mL/min, hemoglobin 9.6 g/dL, total protein 11 g/dL, albumin 3.2 g/dL, immunoglobulin A (IgA) λ M protein 6.8 g/dL, total IgA 7.2 g/dL, IgG 0.4 g/dL, IgM 0.03 g/dL, free κ <0.01 mg/L, free λ 1000 mg/L, free light chain ratio <0.01, β-2–microglobulin 4.2, viscosity 3.0, lactate dehydrogenase 200 U/L, urine protein electrophoresis: 125 mg/dL with 30% M protein, and urine immuno-electrophoresis: λ light chain. Skeletal bone survey showed lytic lesions in femurs and humeri and diffusely in ribs bilaterally as well as compression fractures at T4, T6, and L2. Bone marrow biopsy revealed λ-restricted plasma cells comprising 50% of the bone marrow core. Fluorescence in situ hybridization testing on marrow showed that del(17p) was present in 80% of the plasma cells. Mrs. A. is informed of the diagnosis of multiple myeloma and the need for therapy. She requests consultation with 2 of the leading world experts. However, she wants to be treated near her home and does not want treatment on a clinical trial.
Pluripotency of Wolbachia against Arboviruses: the case of yellow fever
Authors: Rocha Marcele Neves , Duarte Myrian Morato , Mansur Simone Brutman , Silva Bianca Daoud Mafra e , Pereira Thiago Nunes , Adelino Talita Émile Ribeiro , Giovanetti Marta , Alcantara Luis Carlos Junior , Santos Franciele Martins , Costa Victor Rodrigues de Melo , Teixeira Mauro Martins , Iani Felipe Campos de Melo , Costa Vivian Vasconcelos , Moreira Luciano Andrade 
Published: April 2019

Background: Yellow fever outbreaks have re-emerged in Brazil during 2016-18, with mortality rates up to 30%. Although urban transmission has not been reported since 1942, the risk of re-urbanization of yellow fever is significant, as Aedes aegypti is present in most tropical and sub-tropical cities in the World and still remains the main vector of urban YFV. Although the YFV vaccine is safe and effective, it does not always reach populations at greatest risk of infection and there is an acknowledged global shortage of vaccine supply. The introgression of Wolbachia bacteria into Ae. aegypti mosquito populations is being trialed in several countries (www.worldmosquito.org) as a biocontrol method against dengue, Zika and chikungunya. Here, we studied the ability of Wolbachia to reduce the transmission potential of Ae. aegypti mosquitoes for Yellow fever virus (YFV). Methods: Two recently isolated YFV (primate and human) were used to challenge field-derived wild-type and Wolbachia-infected (wMel +) Ae. aegypti mosquitoes. The YFV infection status was followed for 7, 14 and 21 days post-oral feeding (dpf). The YFV transmission potential of mosquitoes was evaluated via nano-injection of saliva into uninfected mosquitoes or by inoculation in mice. Results: We found that Wolbachia was able to significantly reduce the prevalence of mosquitoes with YFV infected heads and thoraces for both viral isolates. Furthermore, analyses of mosquito saliva, through indirect injection into naïve mosquitoes or via interferon-deficient mouse model, indicated Wolbachia was associated with profound reduction in the YFV transmission potential of mosquitoes (14dpf). Conclusions: Our results suggest that Wolbachia introgression could be used as a complementary strategy for prevention of urban yellow fever transmission, along with the human vaccination program.