bluuebunny/crossref_metadata_2025_split huggingface dataset:
AL amyloidosis: from molecular mechanisms to targeted therapies
Authors: Merlini Giampaolo 
Published: April 2019

AbstractSystemic amyloidosis is caused by misfolding and extracellular deposition of circulating proteins as amyloid fibrils, resulting in the dysfunction of vital organs. The most common systemic amyloidosis, light-chain (AL) amyloidosis, is caused by misfolded light chains produced by a small, dangerous B-cell clone. The process of amyloid formation, organ targeting, and damage is multifaceted and, after disease initiation, the complexity of the downstream pathogenic cascade increases, rendering its control a challenge. Because of the progressive nature of the disease, early diagnosis to prevent end-stage organ damage is vital. Improving awareness and systematic use of biomarkers of organ damage in screening populations at risk may improve the still unsatisfactory diagnostic process. Amyloid imaging is now emerging as an important companion of biomarkers in formulating the diagnosis and prognosis and monitoring the effects of therapy. An accurate diagnosis is the basis for appropriate therapy that is risk-adapted and response-tailored. Effective treatments targeting the clone and rapidly and profoundly reducing the amyloid light chains have produced marked improvements in overall survival, making AL amyloidosis the most successful model of all amyloidoses. New therapies targeting the amyloid deposits are now under development, together with novel agents modulating light chain aggregation and proteotoxicity. The future of AL amyloidosis treatment is combination therapy and will require an innovative collaborative model for a rapid translation from bench to bedside with the ultimate aim of achieving a cure for this complex disease.
Novel approaches to therapy in CML
Authors: Bhatia Ravi 
Published: April 2019

Abstract
Treatment with tyrosine kinase inhibitors (TKIs) results in remission and prolongation of survival in most chronic myeloid leukemia (CML) patients but fails to eliminate the leukemia stem cells (LSCs) responsible for disease development and propagation. This accounts for the clinical observation that TKI discontinuation leads to rapid leukemia relapse. Most patients require continued treatment to prevent relapse, with associated risk of relapse, toxicity, teratogenic effects, financial burden, and noncompliance. Understanding LSC resistance to TKI and development of strategies to increase the proportion of CML patients achieving treatment-free remissions is a critical area of investigation in CML. In addition, LSCs are the source of TKI resistance, relapse, or disease progression, which is another major area of need in CML treatment. It is now understood that BCR-ABL kinase-independent mechanisms are responsible for retention of LSC subpopulations. It is likely that both cell-intrinsic and microenvironmental mechanisms contribute to LSC maintenance. Here, we review the current understanding of mechanisms underlying persistence of CML LSCs during TKI treatment, recently described approaches to target these cells and emerging clinical trials, and the challenges impeding more rapid progress in achieving cures for a greater number of CML patients.
When can we stop anticoagulation in patients with cancer-associated thrombosis?
Authors: Lee Agnes Y. Y. 
Published: April 2019

Abstract
The optimal duration of anticoagulant therapy in patients with cancer-associated venous thromboembolism (VTE) is unknown. Without well-designed studies evaluating the efficacy, safety, and cost-effectiveness of continuing anticoagulant therapy beyond the acute treatment period of 3 to 6 months, evidence-based recommendations are lacking. Consensus guidelines generally suggest continuing anticoagulation treatment in patients with active cancer or receiving cancer treatment, with periodic reassessment of the risks and benefits. Unfortunately, with very little published data on the epidemiology of cancer-associated VTE beyond the initial 6 months, it is not possible for clinicians and patients to weigh risks and benefits in a quantitatively informed manner. Further research is needed to provide reliable and contemporary estimates on the risk of recurrent VTE off anticoagulant therapy, risk of bleeding on anticoagulant therapy, case fatality or all-cause mortality, and other important consequences of living with cancer-associated VTE. This chapter provides an overview of the published literature on real-world data on anticoagulant therapy use, the risks and risk factors of recurrent VTE and bleeding, and patient preference and values regarding long-term anticoagulation treatment. It will conclude with a pragmatic, experience-informed approach for tailoring anticoagulant therapy in patients with cancer-associated VTE.
New monogenic disorders identify more pathways to neutropenia: from the clinic to next-generation sequencing
Authors: Corey Seth J. , Oyarbide Usua 
Published: April 2019

Abstract
Neutrophils are the most common type of leukocyte in human circulating blood and constitute one of the chief mediators for innate immunity. Defined as a reduction from a normal distribution of values, neutropenia results from a number of congenital and acquired conditions. Neutropenia may be insignificant, temporary, or associated with a chronic condition with or without a vulnerability to life-threatening infections. As an inherited bone marrow failure syndrome, neutropenia may be associated with transformation to myeloid malignancy. Recognition of an inherited bone marrow failure syndrome may be delayed into adulthood. The list of monogenic neutropenia disorders is growing, heterogeneous, and bewildering. Furthermore, greater knowledge of immune-mediated and drug-related causes makes the diagnosis and management of neutropenia challenging. Recognition of syndromic presentations and especially the introduction of next-generation sequencing are improving the accuracy and expediency of diagnosis as well as their clinical management. Furthermore, identification of monogenic neutropenia disorders is shedding light on the molecular mechanisms of granulopoiesis and myeloid malignancies.
Non–chemotherapy drug–induced neutropenia: key points to manage the challenges
Authors: Curtis Brian R. 
Published: April 2019

AbstractNon–chemotherapy idiosyncratic drug–induced neutropenia (IDIN) is a relatively rare but potentially fatal disorder that occurs in susceptible individuals, with an incidence of 2.4 to 15.4 cases per million population. Affected patients typically experience severe neutropenia within several weeks to several months after first exposure to a drug, and mortality is ∼5%. The drugs most frequently associated with IDIN include metamizole, clozapine, sulfasalazine, thiamazole, carbimazole, amoxicillin, cotrimoxazole, ticlopidine, and valganciclovir. The idiosyncratic nature of IDIN, the lack of mouse models and diagnostic testing, and its low overall incidence make rigorous studies to elucidate possible mechanisms exceptionally difficult. An immune mechanism for IDIN involving neutrophil destruction by hapten (drug)-specific antibodies and drug-induced autoantibodies is frequently suggested, but strong supporting evidence is lacking. Although laboratory testing for neutrophil drug-dependent antibodies is rarely performed because of the complexity and low sensitivity of tests currently in use, these assays could possibly be enhanced by using reactive drug metabolites in place of the parent drug. Patients typically experience acute, severe neutropenia, or agranulocytosis (<0.5 × 109 neutrophils/L) and symptoms of fever, chills, sore throat, and muscle and joint pain. Diagnosis can be difficult, but timely recognition is critical because if left untreated, there is an increase in mortality. Expanded studies of the production and mechanistic role of reactive drug metabolites, genetic associations, and improved animal models of IDIN are essential to further our understanding of this important disorder.
Is molecular remission the goal of multiple myeloma therapy?
Authors: Davies Faith E. 
Published: April 2019

Abstract
The increased number of effective therapies and the wider use of combinations that give deeper remissions have resulted in a reassessment of the goals of myeloma therapy. With the advent of new therapeutic strategies and diagnostic tools, achievement of minimal residual disease (MRD)-negative status has become increasingly important, with some even considering it as the primary endpoint for therapy. The level of MRD that is aimed for is a continuous, rather than an absolute variable, with studies in both transplant-eligible and -noneligible patients showing that the level of MRD achieved is predictive of progression-free survival and overall survival, with an improvement in survival of approximately 1 year for each log-depletion in MRD level. The most widely used methods to assess MRD status include flow cytometry and clonality detection, using next-generation sequencing technologies with sensitivity limits of 1:10−3 to 1:10−6. The timing of when to assess MRD depends on the treatment used, as well as the molecular and cytogenetic subgroup of the myeloma itself. It is also becoming clear that the level of MRD negativity, as well as microenvironmental factors, are important prognostically, including the regeneration of normal plasma cells, and the normalization of the immune repertoire. With advances in antibody-based therapy and immunotherapy, the achievement of stable MRD states is now possible for a significant proportion of patients, and is a prerequisite for myeloma cure.
Iron overload in thalassemia: different organs at different rates
Authors: Taher Ali T. , Saliba Antoine N. 
Published: April 2019

Abstract
Thalassemic disorders lie on a phenotypic spectrum of clinical severity that depends on the severity of the globin gene mutation and coinheritance of other genetic determinants. Iron overload is associated with increased morbidity in both patients with transfusion-dependent thalassemia (TDT) and non–transfusion-dependent thalassemia (NTDT). The predominant mechanisms driving the process of iron loading include increased iron burden secondary to transfusion therapy in TDT and enhanced intestinal absorption secondary to ineffective erythropoiesis and hepcidin suppression in NTDT. Different organs are affected differently by iron overload in TDT and NTDT owing to the underlying iron loading mechanism and rate of iron accumulation. Serum ferritin measurement and noninvasive imaging techniques are available to diagnose iron overload, quantify its extent in different organs, and monitor clinical response to therapy. This chapter discusses the general approach to iron chelation therapy based on organ involvement using the available iron chelators: deferoxamine, deferiprone, and deferasirox. Other novel experimental options for treatment and prevention of complications associated with iron overload in thalassemia are briefly discussed.
Impact of bone disease and pain in thalassemia
Authors: Piga Antonio 
Published: April 2019

AbstractConventional treatment of thalassemia, namely regular blood transfusion and iron chelation, improves perspectives and quality of life; however, successful treatment leads to more time in which long-term complications such as bone disease can develop. Thalassemia bone disease (TBD) is unique: all aspects, from bone anatomy and bone quality to mineral density, may be affected, with important morbidity including osteoporosis, fractures, spinal deformities, nerve compression, and pain. Clinical presentations include growth impairment, rickets-like features, back pain, spinal deformities, any sign of nerve compression, severe osteoporosis, and fragility fractures. Age, history, physical examination, and diagnostic tests support orientation on risk factors. These include bone marrow expansion, toxicity from iron overload and iron chelation, endocrine dysfunctions (hypogonadism, hypohyperparathyroidism, hypothyroidism, growth hormone deficiency, diabetes), and vitamin (D, C, K) and zinc deficiencies. Several of these may coexist in an individual for a long time and at different degrees, making clarification of the relative contribution and selection of the best therapeutic options a challenge. Milestones for prevention of TBD are early and full inhibition of bone marrow hyperplasia and iron toxicity. Empowering patients’ positive resources is key for achieving long-term healthy habits with regard to diet, physical activity, sunlight exposure, and lifestyle. Pain, related or unrelated to bone disease, is frequent in thalassemia. The most important targets for the hematologist include having an expert orientation on disease-related causes of pain, driving differential diagnosis, providing effective pain relief and, where feasible, removing the cause.
New therapeutic targets in transfusion-dependent and -independent thalassemia
Authors: Cappellini M. Domenica , Motta Irene 
Published: April 2019

Abstract
β-Thalassemias are characterized by reduced production of β-globin chain, resulting in α/β-chain unbalance and precipitation of α-globin–heme complexes and determining ineffective erythropoiesis. Ineffective erythropoiesis, chronic hemolytic anemia, and compensatory hematopoietic expansion are the disease hallmarks, and they are related to the severity of the chain unbalance. Several clinical forms of β-thalassemia, including the coinheritance of β-thalassemia with hemoglobin E resulting in hemoglobin E/β-thalassemia, have been described. Clinically, β-thalassemias can be classified as transfusion-dependent thalassemia (TDT) and non–transfusion-dependent thalassemia (NTDT) according to the severity of the phenotype, which is caused by a wide spectrum of mutations in a homozygous or compound heterozygous state. Current treatment of TDT consists of regular transfusions that lead to iron overload, requiring iron chelation to prevent iron-related organ toxicity. NTDT patients do not require transfusions or only occasionally require them; however, they develop iron overload as well because of increased intestinal iron absorption caused by chronic anemia. Hematopoietic stem cell allogenic transplant is the only approved cure for β-thalassemia; however, it is still limited by clinical conditions and the availability of matched donors as well as by potential graft-versus-host disease (GVHD). Gene therapy could avoid the GVHD risk, although hematopoietic stem cells must be genetically modified ex vivo. Epigenetic manipulation and genomic editing are novel experimental approaches. An increased understanding of the pathophysiology that controls the disease process prompted us to explore alternative therapeutic approaches that address the underlying chain unbalance, ineffective erythropoiesis, and iron dysregulation. Molecules, such as JAK2 inhibitors and the activin-receptor ligand trap that target ineffective erythropoiesis, are already in clinical trials with promising results. Other agents aimed to generate iron-restricted erythropoiesis are also under experimental evaluation.
Tailoring front-line therapy in diffuse large B-cell lymphoma: who should we treat differently?
Authors: Davies Andrew 
Published: April 2019

AbstractAlthough there have been significant insights into the biology of diffuse large B-cell lymphoma (DLBCL) over recent years, progress in our therapeutic approach has been disappointing over the same timeframe. This is not for want of trying. In 2017, R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) remains the “gold standard,” despite all of our insights into cell-of-origin and other subgroups. We have traditionally used clinical risk factors to tailor our therapies and have tested intensification of chemotherapy with little success. We are now in an era of testing therapies according to the molecular phenotype of the individual’s tumor. Many phase 1/2 studies have looked at adding targeted agents to conventional R-CHOP with some promise. The phase 3 data are now starting to emerge. Are we ready yet to modify our standard of care and have we reached an era of precision medicine in DLBCL? The answer to this is “not yet.” The exception is perhaps patients with the newly defined World Health Organization category of high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6, the so-called double- and triple-hit lymphomas. In these tumors there has been a move away from R-CHOP to more intensified regimens, however, has not been based upon rigorous prospective evaluation but review of retrospective datasets. This article will review the molecular subgroups of DLBCL, interventional strategies, and the outcomes of these interventions to date.
Current treatment of double hit and double expressor lymphoma
Authors: Reagan Patrick M. , Davies Andrew 
Published: April 2019

Abstract
A 60-year-old female presented with abdominal pain and distension. Following computed tomography scans of the abdomen and pelvis, she was taken urgently to the operating room, with the belief that she had appendicitis with perforation. At laparotomy, the findings were consistent with an ovarian carcinoma; there was extensive infiltration of the ovary, bowel, and omental deposits. Cytoreductive surgery was performed including total abdominal hysterectomy and bilateral salpingo-oophorectomy. The final pathology, however, revealed infiltration with medium-sized atypical lymphoid cells positive for CD20, CD10, MYC, BLC2, and BCL6 by immunohistochemistry. MYC and BCL2 translocations were identified by fluorescence in situ hybridization consistent with a diagnosis of high-grade B-cell lymphoma with rearrangements of MYC and BCL2. With the current data available, what is the optimal treatment of this patient?
Safety profiles of novel agent therapies in CLL
Authors: Ahn Inhye E. , Davids Matthew S. 
Published: April 2019

Abstract
A 70-year-old man with relapsed/refractory chronic lymphocytic leukemia has multiple comorbidities including atrial fibrillation (on warfarin for anticoagulation), irritable bowel syndrome, and chronic renal insufficiency. Two years ago, he received bendamustine and rituximab as first-line therapy for chronic lymphocytic leukemia and achieved partial response, but now has relapsed. Fluorescence in situ hybridization cytogenetics reveals deletion 17p. Which novel agent would you recommend for this patient?
Follicular lymphoma: are we ready for a risk-adapted approach?
Authors: Kahl Brad S. 
Published: April 2019

Abstract
Follicular lymphoma is the most common indolent non-Hodgkin lymphoma in the Western hemisphere. The natural history of FL appears to have been favorably impacted by the introduction of rituximab after randomized clinical trials demonstrated that the addition of rituximab to standard chemotherapy induction has improved the overall survival. Yet, the disease is biologically and clinically heterogeneous with wide variations in outcomes for individual patients. The ability to accurately risk-stratify patients and then tailor therapy to the individual is an area of ongoing research. Historically, tumor grade, tumor burden, and the FL international prognostic index (version 1 and version 2) have been used to distinguish low-risk from high-risk patients. Biologic factors such as mutations in key genes can identify patients at high risk for poor outcomes to first-line therapy (mutational status of 7 genes [EZH2, ARID1A, MEF2B, EP300, FOX01, CREBBP, and CARD11] with Follicular Lymphoma International Prognostic Index). More recently, the quality of the response to initial therapy, as measured by either PET imaging or by remission duration, has been show to identify individuals at high risk. However, several unmet needs remain, including a better ability to identify high-risk patients at diagnosis, the development of predictive biomarkers for targeted agents, and strategies to reduce the risk of transformation.
Management of newly diagnosed immune thrombocytopenia: can we change outcomes?
Authors: Neunert Cindy E. 
Published: April 2019

Abstract
Immune thrombocytopenia resulting from antibody-mediated platelet destruction combined with impaired platelet production is a common cause of thrombocytopenia. The decision to treat newly diagnosed patients is based on several factors including ceasing hemorrhagic manifestations, increasing the platelet count, prevention of bleeding, and inducing remission. Current standard first-line therapy is a course of corticosteroids. Although this treatment paradigm increases the platelet count in the majority of patients, a high percentage relapse after discontinuation of corticosteroid therapy. For this reason, intensification of first-line therapy that results in superior long-term remission rates would be desirable. This manuscript focuses primarily on adults with idiopathic thrombocytopenic purpura (ITP), highlighting pediatric data and practice when applicable. The primary aim is to outline upfront strategies for treatment-naive patients with ITP to enhance remission rates, taking into account assessment of the risks and benefits of these approaches.
Improving Emergency Department-Based Care of Sickle Cell Pain
Authors: Glassberg Jeffrey A. 
Published: April 2019

AbstractPain is the leading cause of emergency department (ED) visits for individuals living with sickle cell disease (SCD). The care that is delivered in the ED is often cited by patients with SCD as the area of health care in greatest need of improvement. In 2014, the National Heart, Lung, and Blood Institute released guidelines for the care of SCD, including recommendations for the management of acute sickle cell pain in the ED. These guidelines provide a framework to understand the elements of ideal emergency sickle cell pain care; however, they do not provide guidance on barriers and facilitators to achieving these ideals in the complex system of the ED. Presented in this article are 4 tenets of implementing guideline-adherent emergency sickle cell care gleaned from the available literature and continuous quality improvement efforts at our institution. These include: (1) strategies to reduce negative provider attitudes toward patients with SCD; (2) strategies to reduce time-to-first-dose of analgesic medication; (3) strategies to improve ED pain care beyond the first dose of medication; and (4) strategies to improve ED patient safety. Application of the principles discussed within can improve patient and provider satisfaction, quality, and safety.
What is the role of screening for pulmonary hypertension in adults and children with sickle cell disease?
Authors: Willen Shaina M. , Gladwin Mark T. 
Published: April 2019

Abstract
Patient case: An 18-year-old male patient with homozygous hemoglobin SS disease was evaluated for progressive dyspnea and elevated tricuspid regurgitant jet velocity (TRV) on echocardiography. The patient’s case is described in detail in Lancet.1 He had been treated with regular transfusions since childhood for stroke, had rare episodes of vaso-occlusive pain episodes, and did not take narcotic pain medications. He presented with progressive severe dyspnea on exertion and lower extremity edema. His laboratory tests were notable for a total hemoglobin level of 11.8 g/dL and hemoglobin S levels <30% but with 18% reticulocytes and elevated markers of hemolysis, such as high plasma levels of lactate dehydrogenase, aspartate amino transferase, and indirect bilirubin. The computed tomography scan of his chest in Figure 1A-B shows a large pulmonary artery, which has a greater diameter than his aorta, and a mosaic perfusion pattern, typical for severe pulmonary arterial hypertension. His Doppler echocardiographic study (Figure 1C) showed an unusually high TRV of 5.93 m/s, consistent with a calculated pulmonary artery systolic pressure of >140 mm Hg (4 times the TRV squared = 4V2). Additional images in Figure 1D show a dilated right ventricle and right atrium with a compressed left ventricle. The patient’s right heart catheterization revealed a pulmonary artery systolic pressure of 147 mm Hg and diastolic pressure of 49 mm Hg; note that the normal values are ∼25/10 mm Hg.