bluuebunny/crossref_metadata_2025_split huggingface dataset:
How to approach thrombocytopenia
Authors: Stasi Roberto 
Published: October 2019

AbstractThrombocytopenia is a common hematologic finding with variable clinical expression. A low platelet count may be the initial manifestation of infections such as HIV and hepatitis C virus or it may reflect the activity of life-threatening disorders such as the thrombotic microangiopathies. A correct identification of the causes of thrombocytopenia is crucial for the appropriate management of these patients. In this review, we present a systematic evaluation of adults with thrombocytopenia. The approach is clearly different between outpatients, who are frequently asymptomatic and in whom we can sometimes indulge in sophisticated and relatively lengthy investigations, and the dramatic presentation of acute thrombocytopenia in the emergency department or in the intensive care unit, which requires immediate intervention and for which only a few diagnostic tests are available. A brief discussion of the most common etiologies seen in both settings is provided.
The many faces of common variable immunodeficiency
Authors: Cunningham-Rundles Charlotte 
Published: October 2019

Abstract
Common variable immunodeficiency (CVID) is a rare immune deficiency characterized by low levels of serum IgG, IgA, and/or IgM, with a loss of Ab production. The diagnosis is most commonly made in adults between the ages of 20 and 40 years, but both children and much older adults can be found to have this immune defect. The range of clinical manifestations is broad, including acute and chronic infections, inflammatory and autoimmune diseases, and an increased incidence of cancer and lymphoma. For all of these reasons, the disease phenotype is both heterogeneous and complex. In the past few years, data from large patient registries have revealed that both selected laboratory markers and clinical phenotyping may aid in separating groups of subjects into biologically relevant categories. CVID consists of 2 phenotypes, 1 in which infections are the characteristic and another in which impressive inflammatory and/or hematologic complications also develop, including lymphadenopathy, splenomegaly, autoimmune cytopenias, enteropathy, and/or and granulomatous disease. These phenotypes appear to be stable, are related to immunologic and inflammatory markers, and are predictive of outcomes. This review outlines current understanding about this syndrome based on studies of large cohorts, highlighting the evaluation and treatment of complications and, in particular, the autoimmune and inflammatory conditions that affect these patients.
Pathogenesis in immune thrombocytopenia: new insights
Authors: Johnsen Jill 
Published: October 2019

AbstractIdiopathic (immune) thrombocytopenic purpura (ITP) is a common autoimmune disorder resulting in isolated thrombocytopenia. ITP can present either alone (primary) or in the setting of other conditions (secondary) such as infections or altered immune states. ITP is associated with a loss of tolerance to platelet antigens and a phenotype of accelerated platelet destruction and impaired platelet production. Although the etiology of ITP remains unknown, complex dysregulation of the immune system is observed in ITP patients. Antiplatelet antibodies mediate accelerated clearance from the circulation in large part via the reticuloendothelial (monocytic phagocytic) system. In addition, cellular immunity is perturbed and T-cell and cytokine profiles are significantly shifted toward a type 1 and Th17 proinflammatory immune response. Further clues into immune dysregulation in ITP may be gleaned from studies of secondary ITP. Some infections can induce antiplatelet Abs by molecular mimicry, and there may be common elements involved in breaking tolerance with other autoimmune disorders. There is also evidence for a genetic predisposition to both ITP and responsiveness to therapy, which may in part lie within immune-related genes. Lastly, treatment with immunomodulatory agents remains the mainstay of ITP therapies.
What is the evidence for the use of bisphosphonate therapy in newly diagnosed multiple myeloma patients lacking bone disease?
Authors: Locke Frederick L. , Morgan Gareth J. 
Published: October 2019

Abstract
A 55-year-old man without prior medical problems presented to the emergency room with a 2-month history of progressive fatigue. Initial workup showed a hemoglobin level of 9.0 g/dL and an increased total protein level of 12.6 g/dL. Further testing revealed a normal serum calcium and creatinine, an IgG kappa paraprotein of 5.4 g/dL, and a Bence Jones proteinuria of 450 mg of kappa light chain in 24 hours. The bone marrow showed 60% plasma cells with normal cytogenetics and t(4;14), but no other associated genetic abnormalities by FISH. Skeletal survey and MRI of the spine were negative for myeloma bone disease. The patient's oncologist recently began therapy with lenalidomide, bortezomib, and dexamethasone and recommended the initiation of zoledronic acid monthly. The patient questions the benefit of this drug because he has no bone disease.
Interim PET-CT in the management of diffuse large B-cell lymphoma
Authors: Moskowitz Craig H. 
Published: October 2019

Abstract
Once the diagnosis of diffuse large B-cell lymphoma has been established, physicians and patients would like to know if a given treatment regimen is likely to succeed—if the patient can be cured or if at least a durable remission is achievable. This desire has lead to efforts to use interim positron emission tomography (PET) scanning as part of risk-adapted therapeutic clinical trials. In general, these studies use a variable number of doxorubicin-based induction cycles with rituximab, followed by the interim PET. If the test is negative, treatment is continued, but if it is positive, therapy is changed to treatment that concludes with autologous stem cell transplantation. Results of studies for interim PET have yielded mixed and confusing results, with high negative predictive value but positive predictive value ranging from 20%-80%. To use interim PET scanning effectively, clinicians need simple (positive or negative) criteria that are easy to interpret, reproducible, and have a high positive and negative predictive value so that we can be certain that by not changing therapy if the test is positive, we are not doing the patient a disservice.
Is there any role for transplantation in the rituximab era for diffuse large B-cell lymphoma?
Authors: Gisselbrecht Christian 
Published: October 2019

Abstract
Salvage chemotherapy followed by high-dose therapy and autologous stem cell transplantation is the standard of treatment for chemosensitive relapses in diffuse large B-cell lymphoma. The addition of rituximab to chemotherapy has improved the response rate and failure-free survival after first-line treatment and relapses. Fewer relapses are expected, although there is no consensus on the best salvage regimen. The intergroup Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) set the limits for this standard of treatment after first comparing 2 salvage regimens: rituximab, ifosfamide, etoposide, and carboplatin (R-ICE) and rituximab, dexamethasone, aracytine, and cisplatin (R-DHAP). There was no difference in response rates or survivals between these salvage regimens. Several factors affected survival: prior treatment with rituximab, early relapse (< 12 months), and a secondary International Prognostic Index score of 2-3. For patients with 2 factors, the response rate to salvage was only 46%, which identified easily a group with poor outcome. Moreover, patients with an ABC subtype or c-MYC translocation responded poorly to treatment. More than 70% of patients will not benefit from standard salvage therapy, and continued progress is needed. Studies evaluating immunotherapy after transplantation, including allotransplantation, new conditioning regimens with radioimmunotherapy and other combinations of chemotherapy based on diffuse large B-cell lymphoma subtype, are discussed herein. Early relapses and/or patients refractory to upfront rituximab-based chemotherapy have a poor response rate and prognosis. A better biological understanding of these patients and new approaches are warranted.
Changing role of stem cell transplantation in follicular lymphoma
Authors: Laport Ginna G. 
Published: October 2019

AbstractPatients with advanced follicular lymphoma (FL) have numerous treatment options, including observation, radiotherapy, single-agent or combination chemotherapy, mAbs, and radioimmunoconjugates. These therapies can extend progression-free survival but none can provide a cure. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curable therapy for FL, with the field shifting more toward the use of reduced-intensity conditioning regimens because of the lower associated nonrelapse mortality compared with myeloablative regimens. However, GVHD and infection are still problematic in the allo-HSCT population. Autologous HSCT (auto-HSCT) confers high response rates and prolongs progression-free survival in relapsed patients who are chemosensitive, and an increasing amount of data suggest that auto-HSCT may be curative if offered to relapsed patients who are not heavily pretreated. Auto-HSCT has no role as consolidation therapy for patients in first remission based on the results from 3 large randomized trials. Novel conditioning regimens with radioimmunoconjugates have been used in both auto-HSCT and allo-HSCT regimens and results have shown efficacy even in chemorefractory patients. Therefore, with the exception of patients in first remission, the optimal timing for HSCT remains controversial. However, the outcomes seen after auto-HSCT and allo-HSCT continue to improve, and HSCT represents a treatment modality that should be considered in all FL patients, especially while their disease remains chemoresponsive.
Platelets in the neonatal period: developmental differences in platelet production, function, and hemostasis and the potential impact of therapies
Authors: Sola-Visner Martha 
Published: October 2019

AbstractThrombocytopenia is a common problem among sick neonates admitted to the neonatal intensive care unit. Frequently, platelet transfusions are given to thrombocytopenic infants in an attempt to decrease the incidence or severity of hemorrhage, which is often intracranial. Whereas there is very limited evidence to guide platelet transfusion practices in this population, preterm infants in the first week of life (the highest risk period for bleeding) are nearly universally transfused at higher platelet counts than older infants or children. To a large extent, this practice has been influenced by the observation that neonatal platelets are hyporeactive in response to multiple agonists in vitro, although full-term infants exhibit normal to increased primary hemostasis. This apparently paradoxical finding is due to factors in the neonatal blood that enhance the platelet-vessel wall interaction and counteract the platelet hyporeactivity. Relatively few studies have evaluated the platelet function and primary hemostasis of preterm infants, the subset of neonates at highest risk of bleeding and those most frequently transfused. Current understanding of platelet production and function in preterm and full-term neonates, how these factors affect their response to thrombocytopenia and their primary hemostasis, and the implications of these developmental differences to transfusion medicine are reviewed herein.
New oral anticoagulants: which one should my patient use?
Authors: Weitz Jeffrey I. , Gross Peter L. 
Published: October 2019

Abstract
The new oral anticoagulants are rapidly replacing warfarin for several indications. In contrast to warfarin, which lowers the functional levels of all of the vitamin K-dependent clotting factors, the new agents target either factor Xa or thrombin. With targeted inhibition of coagulation, the new oral anticoagulants have pharmacologic and clinical features that distinguish them from warfarin. Focusing on these features, this paper (a) compares the pharmacology of the new oral anticoagulants with that of warfarin (b) identifies the class effects of these drugs and their differentiating features, (c) reviews their current indications, and (d) uses this information to help clinicians make informed decisions regarding the choice of the right anticoagulant for the right patient.
The spectrum of JAK2-positive myeloproliferative neoplasms
Authors: Kiladjian Jean-Jacques 
Published: October 2019

Abstract
The discovery of the JAK2V617F mutation triggered an unexpected flowering of basic and clinical studies in the field of myeloproliferative neoplasms (MPNs), resulting after just a few years in an exceptional amount of new information. One important consequence of those new findings was the modification of the World Health Organization classification and diagnostic algorithms for these diseases, which is still based on the original concept developed by William Dameshek in 1951 and keeps distinct entities under the umbrella of classical Philadelphia-negative MPNs. These MPNs are essential thrombocythemia, polycythemia vera, and primary myelofibrosis. Could a new molecular classification be a better tool to manage MPN patients? Several studies have shown that essential thrombocythemia and primary myelofibrosis can be divided into distinct subtypes based on the presence of the JAK2V617F mutation. Can we now define JAK2-positive diseases to depict a distinct entity from JAK2-negative MPNs? This chapter reviews the significance of JAK2 mutation positivity in the diagnosis, prognosis, and therapy of MPNs.
Is there a role for the use of IFN-α in primary myelofibrosis?
Authors: Nguyen Huong (Marie) , Kiladjian Jean-Jacques 
Published: October 2019

AbstractA 62-year-old man with a history of diabetes and hypertension is referred to your hematology clinic for an incidental discovery of anemia. He does not have any constitutional symptoms and previous blood counts have been within the normal range. He has hepatosplenomegaly with a palpable spleen of 6 cm below the left costal margin and a liver size of 2.5 cm below the right costal margin. Laboratory evaluation shows a WBC count of 12.8 K/μL, hemoglobin of 11.0 g/dL, and platelets of 202 K/μL, with a mean corpuscular volume of 85.7, 72% neutrophils, 13% lymphocytes, 4% monocytes, 5% eosinophils, 1% basophils, 1% promyelocytes, 4% myelocytes, and lactate dehydrogenase of 447 U/L (upper limit of normal is < 340 U/L). Peripheral blood smear shows 2+ teardrop-shaped RBCs, large hypogranular platelets, and rare nucleated RBCs. Bone marrow (BM) biopsy exhibits a hypercellular BM with atypical megakaryocytes and increased reticulin fibrosis (MF-1). BCR-ABL gene rearrangement by FISH was negative and JAK2 V617F mutation was 95% positive. He was diagnosed with primary myelofibrosis considered low risk (risk score of 0) by the International Prognostic Scoring System.1 Because he is low risk and asymptomatic, he does not need treatment at this time.2 However, he has read about the possible clinical benefits of IFN-α and its potential reduction of BM fibrosis and wonders whether this would be an appropriate treatment.
Diagnostic and therapeutic challenges in the thrombotic thrombocytopenic purpura and hemolytic uremic syndromes
Authors: George James N. , Al-Nouri Zayd L. 
Published: October 2019

Abstract
Evaluation and management of patients with suspected thrombotic thrombocytopenic purpura (TTP) continue to be a critical challenge for hematologists. The diagnostic criteria are not precise, often causing uncertainty about whether it is appropriate to initiate plasma exchange (PEX), the essential treatment for TTP. Initiation of PEX remains a clinical decision; severe ADAMTS13 (< 10% activity) deficiency alone is neither sufficiently sensitive nor specific for the diagnosis of TTP. However, patients who do have severe acquired ADAMTS13 deficiency define the characteristic clinical features of TTP, the response to treatment, and the long-term outcomes. Patients with severe acquired ADAMTS13 deficiency are predominantly young women and the relative frequency of blacks is increased. Patients may present with only microangiopathic hemolytic anemia and thrombocytopenia, neurologic and renal abnormalities are often not present, fever rarely occurs; the complete “pentad” of these clinical features almost never occurs in current practice. Response to PEX is typically rapid but may not be sustained when PEX is stopped. Use of corticosteroids and rituximab has decreased the number of PEX treatments required to achieve a remission and has resulted in fewer PEX-related major complications. Relapse (in approximately 40% of patients) may be the most apparent risk after recovery, but long-term health outcomes are also very important. Minor cognitive abnormalities are common, the frequency of depression is increased, and the frequency of hypertension is increased. Careful long-term follow-up of TTP patients is essential.
Implications of new prognostic markers in chronic lymphocytic leukemia
Authors: Chiorazzi Nicholas 
Published: October 2019

AbstractSeveral prognostic markers based on genetic, phenotypic, and molecular characteristics of chronic lymphocytic leukemia (CLL) B cells have emerged in the past decade. The clinical utility of these newer prognostic indicators, alone or in combination with each other and other clinical predictive systems, is still being determined. This chapter attempts to define biologic and molecular underpinnings of 3 sets of prognostic indicators in CLL: genetic abnormalities quantified by FISH and/or defined by exploratory sensitive molecular techniques, expression of specific proteins in or on CLL cells (ie, CD38, CD49d, and ZAP-70), and the IGHV mutation status of a CLL clone. Although not demonstrated conclusively, each probably reflects the biologic properties of the leukemic cells of individual CLL patients. This reflection may be direct, indicating a specific property of the CLL cell itself, or indirect, representing how the CLL cell interacts with the host's microenvironment. The new tyrosine kinase inhibitors that are currently in clinical trials support this interpretation. These and other biology-based indicators of patient clinical course and outcome can be used as starting points from which to understand and treat CLL.
Monitoring and reversal of direct oral anticoagulants
Authors: Cuker Adam , Siegal Deborah 
Published: October 2019

AbstractAlthough the direct oral anticoagulants (DOACs) do not require routine monitoring and reduce bleeding compared with warfarin, there are special circumstances in which laboratory measurement or reversal of their anticoagulant effect may be indicated. The dilute thrombin time and ecarin-based assays are able to quantify dabigatran across a broad range of concentrations, but are not widely available. A normal thrombin time excludes clinically relevant levels and a normal activated partial thromboplastin time probably excludes excess levels of dabigatran. Factor Xa inhibitors may be quantified with an anti-Xa assay calibrated with drug-specific standards. A normal prothrombin time probably excludes excess levels of rivaroxaban and edoxaban, but not apixaban. Patients with minor and moderate DOAC-associated bleeding can be treated with supportive care and general hemostatic measures. Nonspecific reversal agents (eg, prothrombin complex concentrate, activated prothrombin complex concentrate) are of unproven benefit, carry a risk of thrombosis, and should be reserved for severe bleeding. Specific reversal agents, such as idarucizumab (a monoclonal antibody fragment that binds dabigatran) and andexanet alfa (a recombinant factor Xa variant that binds factor Xa inhibitors but lacks coagulant activity), are in clinical development.
Uncommon histiocytic disorders: Rosai–Dorfman, juvenile xanthogranuloma, and Erdheim–Chester disease
Authors: Haroche Julien , Abla Oussama 
Published: October 2019

Abstract
Rosai–Dorfman disease (RDD), juvenile xanthogranuloma (JXG), and Erdheim–Chester disease (ECD) are non-Langerhans cell (non-LCH) disorders arising from either a dendritic or a macrophage cell. RDD is a benign disorder that presents with massive lymphadenopathy, but can have extranodal involvement. In most cases, RDD is self-limited and observation is the standard approach. Treatment is restricted to patients with life-threatening, multiple-relapsing, or autoimmune-associated disease. JXG is a pediatric histiocytosis characterized by xanthomatous skin lesions that usually resolve spontaneously. In a minority of cases, systemic disease can occur and can be life threatening. Juvenile myelomonocytic leukemia (JMML), as well as germline mutations in NF1 and NF2, have been reported in children with JXG. Recent whole-exome sequencing of JXG cases did not show the BRAF-V600E mutation, although 1 patient had PI3KCD mutation. ECD is an adult histiocytosis characterized by symmetrical long bone involvement, cardiovascular infiltration, a hairy kidney, and retroperitoneal fibrosis. Central nervous system involvement is a poor prognostic factor. Interferon-α is the standard as front-line therapy, although cladribine and anakinra can be effective in a few refractory cases. More than one-half of ECD patients carry the BRAF-V600E mutation. Currently, >40 patients worldwide with multisystemic, refractory BRAF-V600E+ ECD have been treated with vemurafenib, a BRAF inhibitor, which was found to be highly effective. Other recurrent mutations of the MAP kinase and PI3K pathways have been described in ECD. These discoveries may redefine ECD, JXG, and LCH as inflammatory myeloid neoplasms, which may lead to new targeted therapies.
FURTHER OBSERVATIONS ON THE EFFECT OF BENZENE ON A STRAIN OF MYELOID CHLOROLEUKEMIA IN MICE AND ON CHANGES PRODUCED IN THE LEUKEMIC CELLS BY THE CHEMICAL
Authors: FLORY C. M. , STEINHARDT I. D. , FURTH J. 
Published: October 2019

Abstract
Oral administration of 5 mg. of benzene six times weekly to 46 mice that had been injected 24 hours before with the cells of the myeloid chloroleukemia 1394, considerably prolonged the survival of the animals, and in 16 of these mice it seemed to prevent the development of the disease. The spleens of the animals so treated increased in size at a much slower rate than those of the untreated animals, and the leukemic infiltration of the organs was delayed.
Five mg. of benzene given in a similar manner to mice with advanced chloroleukemia likewise prolonged the survival time of the mice and also slowed the rate of increase of the size of the spleens; 25 mg. given five times in a 6 day period to mice with this leukemia brought about a marked reduction in the size of the spleens. Further treatments slowed the rate of enlargement of the spleens and survival was prolonged.
In 8 mice bearing subcutaneous tumors composed of the cells of the chloroleukemia the oral administration of 25 mg. of benzene five times in a 6 day period followed by 5 mg. given six times weekly brought about the disappearance of the local tumors as determined by palpation, but in 6 mice the tumors recurred and killed the animals. Microscopic examination of tumors of mice treated with benzene showed advanced degenerative changes in leukemic cells.
A Histochemical Procedure for Localizing and Evaluating Leukocyte Alkaline Phosphatase Activity in Smears of Blood and Marrow
Authors: KAPLOW LEONARD S. 
Published: October 2019

Abstract
A rapid and simple method is described for demonstrating the presence of alkaline phosphatase activity in cells of blood and bone marrow. Smears were fixed with 10 per cent formalin in methanol at 0 ± 5 C. for 30 seconds and stained by the azo dye procedure, using propanediol buffer at a pH of 9.6.
A "scoring" technic is outlined, which permits the comparison of alkaline phosphatase activities of blood leukocytes of different individuals.
Alkaline phosphatase activity was found only in neutrophilic granulocytes and was localized exclusively in the cytoplasm of these cells. In normal adults, 43 to 95 per cent (mean of 78%) of all neutrophils were unstained. Staining was up to ten times more intense in smears from patients with a variety of pathologic disorders.