bluuebunny/crossref_metadata_2025_split huggingface dataset:
Iron age: novel targets for iron overload
Authors: Casu Carla , Rivella Stefano 
Published: November 2014

Abstract
Excess iron deposition in vital organs is the main cause of morbidity and mortality in patients affected by β-thalassemia and hereditary hemochromatosis. In both disorders, inappropriately low levels of the liver hormone hepcidin are responsible for the increased iron absorption, leading to toxic iron accumulation in many organs. Several studies have shown that targeting iron absorption could be beneficial in reducing or preventing iron overload in these 2 disorders, with promising preclinical data. New approaches target Tmprss6, the main suppressor of hepcidin expression, or use minihepcidins, small peptide hepcidin agonists. Additional strategies in β-thalassemia are showing beneficial effects in ameliorating ineffective erythropoiesis and anemia. Due to the suppressive nature of the erythropoiesis on hepcidin expression, these approaches are also showing beneficial effects on iron metabolism. The goal of this review is to discuss the major factors controlling iron metabolism and erythropoiesis and to discuss potential novel therapeutic approaches to reduce or prevent iron overload in these 2 disorders and ameliorate anemia in β-thalassemia.
Detection and management of minimal residual disease in acute lymphoblastic leukemia
Authors: Schrappe Martin 
Published: November 2014

Abstract
The detection of minimal residual disease (MRD) has become part of the state-of-the-art diagnostics to guide treatment both in pediatric and adult acute lymphoblastic leukemia (ALL). This applies to the treatment of de novo and recurrent ALL. In high-risk ALL, MRD detection is considered an important tool to adjust therapy before and after hematopoietic stem cell transplantation. Precise quantification and quality control is instrumental to avoid false treatment assignment. A new methodological approach to analyzing MRD has become available and is based on next-generation sequencing. In principle, this technique will be able to detect a large number of leukemic subclones at a much higher speed than before. Carefully designed prospective studies need to demonstrate concordance or even superiority compared with those techniques in use right now: detection of aberrant expression of leukemia-specific antigens by flow cytometry of blood or bone marrow, or detection of specific rearrangements of the T-cell receptor or immunoglobulin genes by real-time quantitative polymerase chain reaction using DNA of leukemic cells. In some cases with known fusion genes, such as BCR/ABL, reverse transcriptase-polymerase chain reaction has been used as additional method to identify leukemic cells by analyzing RNA in patient samples. MRD detection may be used to modulate treatment intensity once it has been demonstrated at well-defined informative checkpoints that certain levels of MRD can reliably predict the risk of relapse. In addition, MRD is used as end point to determine the activity of a given agent or treatment protocol. If activity translates into antileukemic efficacy, MRD may be considered a surrogate clinical end point.
The evolving genomic landscape of myeloproliferative neoplasms
Authors: Nangalia Jyoti , Green Tony R. 
Published: November 2014

Abstract
Our understanding of the genetic basis of the Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) has moved forward at a staggering pace over the last decade. With the discoveries of underlying mutations in JAK2, MPL, and, most recently, calreticulin (CALR), that together account for ∼90% of patients with MPNs, these conditions are now among the best characterized of hematological malignancies. While JAK-STAT pathway activation has been shown to be central to the pathogenesis of the MPN phenotype, the mechanism by which mutant CALR alters cellular function to result in myeloid proliferation remains unclear. Other mutations in several epigenetic modifiers, such as ASXL1, DNMT3a, TET2, EZH2, IDH1, and IDH2, as well as in genes involved in mRNA splicing, such as SF3B1 and U2AF2, have also been described in recent years in patients with MPNs, and evidence is emerging as to how these may be contributing to disease biology. From a therapeutic perspective, the discovery of aberrations in JAK2 has rapidly translated into the successful clinical use of JAK inhibitors in MPNs. Mutant calreticulin has the potential to be a tumor-specific therapeutic target because the mutations generate a novel protein C-terminus. In this chapter, we detail the genomic alterations that underlie MPNs, with a focus on the recent discovery of mutations in CALR, and explore the clinical and biological relevance of the altered genomic landscape in MPNs.
Laboratory methods to detect antiphospholipid antibodies
Authors: Krilis Steven A. , Giannakopoulos Bill 
Published: November 2014

Abstract
This chapter reviews several important themes pertaining to the antiphospholipid syndrome (APS), including a description of the clinical features, a discussion of the main autoantigen, beta 2-glycoprotein I (β2GPI), and insights into the characteristics of the pathogenic anti-β2GPI autoantibodies. Evidence-based considerations for when to test for APS are explored, along with the clinical significance of patients testing positive on multiple APS assays, so-called triple positivity. A detailed review of recently published laboratory guidelines for the detection of lupus anticoagulant and the solid-phase anticardiolipin and anti-β2GPI ELISAs is undertaken. Finally, a brief review of nonclassification criteria laboratory assays with potential future diagnostic utility is presented.
Lasting power of new clotting proteins
Authors: Powell Jerry S. 
Published: November 2014

AbstractHemophilia is a genetic disease caused by a deficiency of one of the coagulation proteins. The term usually refers to either hemophilia A, factor VIII (FVIII), with an incidence of ∼1 in 5000 male births, or hemophilia B, factor IX (FIX), with an incidence of ∼1 in 30 000 male births. When severe, the disease leads to spontaneous life-threatening bleeding episodes. Current therapy requires frequent intravenous infusions of therapeutic factor concentrates. Most patients administer the infusions at home every few days and must limit their physical activities to avoid bleeding when the factor activity levels are below normal. In March 2014, a new therapeutic FIX preparation was approved for clinical use in Canada and the United States and, in June 2014, a new FVIII preparation was approved for clinical use in the United States. Over the next couple of years, other new factor products for FIX, FVIIa, and FVIII, which are currently in late stages of clinical trials, will likely also be approved. These new factors have been engineered to extend their half-life in circulation, thus providing major therapeutic advances for patients with hemophilia primarily by allowing treatment with fewer infusions per month. In the clinical trials so far, >500 patients have successfully used these extended half-life products regularly for >1 year to prevent spontaneous bleeding, to treat successfully any bleeding episodes, and to provide effective coagulation for major surgery. Essentially all infusions were well tolerated and effective. These promising new therapies should allow patients to use fewer infusions to maintain appropriate clotting factor activity levels in all clinical settings.
Pulmonary hypertension in sickle cell disease: diagnosis and management
Authors: Ataga Kenneth I. , Klings Elizabeth S. 
Published: November 2014

AbstractThe increased survival of patients with sickle cell disease (SCD) into adulthood is associated with an increased incidence of multiorgan dysfunction and a progressive systemic and pulmonary vasculopathy. The high prevalence of an elevated tricuspid regurgitant jet velocity and its association with an increased risk of death in adult patients is well established. However, there has been controversy regarding the prevalence of pulmonary hypertension (PH) and its association with mortality in SCD. Multiple recently published reports demonstrate that PH as diagnosed by right heart catheterization is common in adult SCD patients, with a prevalence of 6%–11%. Furthermore, PH is associated with an increased risk of death in SCD patients. In this chapter, we provide evidence for the high prevalence of PH in SCD and its association with mortality and make recommendations for its evaluation and management. Finally, we provide the rationale for screening for this life-threatening complication in adult patients with SCD.
Red cell exchange: special focus on sickle cell disease
Authors: Kim Haewon C. 
Published: November 2014

Abstract
The primary function of red blood cells (RBCs) is to deliver oxygen from the lungs to tissues. Tissue hypoxia occurs when the oxygen-carrying capacity of RBCs is compromised due primarily to 3 causes: (1) a reduction in circulating RBC mass, (2) an increase in circulating RBC mass, or (3) abnormal hemoglobin (Hb) that either does not sufficiently release oxygen to tissues (high-oxygen-affinity hemoglobin) or occludes the microvasculature due to deformed RBCs (sickled RBCs). To improve oxygenation in patients with reduced or increased RBC mass, RBC administration (simple transfusion) or RBC removal (RBC depletion) is performed, respectively. However, for patients with abnormal Hb, RBCs containing abnormal Hb are removed and replaced by healthy volunteer donor RBCs by red cell exchange (RCE). RCE can be performed by manual exchange or by automated exchange using a blood cell separator (erythrocytapheresis). In this review, indications for RCE in sickle cell disease using the evidence-based American Society for Apheresis categories1 are presented and the rationale for RCE in each disorder are discussed. Simple transfusion versus RCE and manual RCE versus automated RCE are compared. Finally, this review briefly presents some of the challenges of performing erythrocytapheresis in small children and discusses various choices for central venous access during RCE.2
Clinical and laboratory diagnosis of VWD
Authors: Federici Augusto B. 
Published: November 2014

AbstractVWD is the most common inherited bleeding disorder and is due to a deficiency and/or abnormality of VWF. VWD is inherited in an autosomal-dominant or autosomal-recessive pattern, but women are apparently more symptomatic. Three main criteria are required for correct diagnoses of VWD: (1) positive bleeding history since childhood, (2) reduced VWF activity in plasma, and (3) history of bleeding in the family. The bleeding score, together with baseline VWF levels and family history, have been proposed as more evidence-based criteria for VWD. Measurements of a reduced VWF activity in plasma are essential for the diagnosis of VWD; assays for the evaluation of the interactions between VWF and platelet glycoprotein Ib receptor with or without ristocetin, as well as VWF collagen binding, are currently in use. However, other tests such as VWF antigen, factor VIII, ristocetin-induced platelet agglutination, multimeric analysis, VWF propeptide, VWF/FVIII binding assay, and assessment of biological response to desmopressin are necessary to characterize VWD types. Levels of VWF activities <30 U/dL have been associated with a bleeding phenotype and the presence of mutations in the VWF gene.
Transfusion strategies in hematologic and nonhematologic disease
Authors: Carson Jeffrey L. , Strair Roger 
Published: November 2014

Abstract
Substantial progress has been made in our understanding of the risks and benefits of RBC transfusion through the performance of large clinical trials. More than 7000 patients have been enrolled in trials randomly allocating patients to higher transfusion thresholds (∼9-10 g/dL), referred to as liberal transfusion, or lower transfusion thresholds (∼7-8 g/dL), referred to as restrictive transfusion. The results of most of the trials suggest that a restrictive transfusion strategy is safe and, in some cases, superior to a liberal transfusion strategy. However, in patients with myocardial infarction, brain injury, stroke, or hematological disorders, more large trials are needed because preliminary evidence suggests that liberal transfusion might be beneficial or trials have not been performed at all.
Maximizing GVL in allogeneic transplantation: role of donor lymphocyte infusions
Authors: Nikiforow Sarah , Alyea Edwin P. 
Published: November 2014

Abstract
Donor lymphocyte infusions (DLIs) can induce complete and durable remissions in some patients with hematologic malignancies who have relapsed after allogeneic transplantation, providing definitive evidence of a GVL effect. Despite the great promise initially envisioned for DLI as a method to augment GVL after transplantation, it utility is limited by low response rates in diseases other than chronic myelogenous leukemia and by the development of GVHD, the principal complication of DLI. To maximize GVL potency while minimizing toxicity, cellular effectors active in GVL need to be elucidated. Insight into mechanisms of GVL, such as reversal of in situ T-cell exhaustion, may allow identification of patients who will respond to DLI based on the presence of tumor-infiltrating lymphocytes in the BM. Understanding the clinical factors that influence the effectiveness and abrogate the toxicity of DLI, such as cell dose and timing of DLI after transplantation, will allow further optimization of DLI. This chapter reviews novel strategies that maximize the GVL effect of DLI by enhancing activity while limiting toxicity.
Epidemiologic and clinical data linking factors XI and XII to thrombosis
Authors: Key Nigel S. 
Published: November 2014

Abstract
Currently available evidence supports the contention that elevated levels of factor XI (fXI) are associated with a greater risk of venous thromboembolism and ischemic stroke, but, less convincingly, with myocardial infarction. Conversely, reduced plasma levels of fXI seem to offer some protection from venous thromboembolism and stroke, but not myocardial infarction. Factor XI-deficient patients are at risk for certain types of bleeding, particularly posttraumatic hemorrhage on mucosal surfaces where there is a high endogenous fibrinolytic activity. In contrast, the situation with fXII in human thrombosis remains enigmatic. Deficiency of fXII is clearly not associated with any bleeding risk, but neither does it seem to be protective against thrombosis. The longstanding debate as to whether partial fXII deficiency represents a risk factor for thrombosis remains unresolved, with seemingly conflicting results depending on study design, type of assay used, and analyte evaluated. The possibility that elevated fXII levels represent a risk factor for thrombosis is not borne out in the literature.
Established and novel agents for myelodysplastic syndromes
Authors: Sekeres Mikkael A. , Gerds Aaron T. 
Published: November 2014

Abstract
The myelodysplastic syndromes (MDS) are the most commonly diagnosed myeloid malignancy, with >15 000 new cases identified in the United States yearly. Prognostic scoring systems supplant a formal staging approach and, in general, divide patients into those with lower-risk and those with higher-risk MDS. Although treatment goals for patients with lower-risk disease focus on minimizing transfusions and optimizing quality of life, in higher-risk MDS, the goal is to delay transformation to acute leukemia and to prolong survival. In lower-risk patients, isolated cytopenias are treated with erythropoiesis-stimulating agents or growth factors such as thrombopoietin mimetics. For patients with the del(5q) cytogenetic abnormality or those who fail these initial approaches, lenalidomide may be tried, as can experimental agents. Lower-risk patients with multiple cytopenias may be treated with immunosuppressive drugs or low-dose hypomethylating agents. For patients with higher-risk disease, hypomethylating agents are the preferred initial treatment approach, with evaluation for hematopoietic cell transplantation at diagnosis. Several novel agents are being developed for MDS patients who have failed hypomethylating drugs.
Diagnosis of ‘double hit’ diffuse large B-cell lymphoma and B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma: when and how, FISH versus IHC
Authors: Swerdlow Steven H. 
Published: November 2014

Abstract
Identification of large B-cell lymphomas that are “extra-aggressive” and may require therapy other than that used for diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), is of great interest. Large B-cell lymphomas with MYC plus BCL2 and/or BCL6 rearrangements, so-called ‘double hit’ (DHL) or ‘triple hit’ (THL) lymphomas, are one such group of cases often recognized using cytogenetic FISH studies. Whether features such as morphologic classification, BCL2 expression, or type of MYC translocation partner may mitigate the very adverse prognosis of DHL/THL is controversial. Classification of the DHL/THL is also controversial, with most either dividing them up between the DLBCL, NOS and B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and Burkitt lymphoma (BCLU) categories or classifying at least the majority as BCLU. The BCLU category itself has many features that overlap those of DHL/THL. Currently, there is growing interest in the use of MYC and other immunohistochemistry either to help screen for DHL/THL or to identify “double-expressor” (DE) large B-cell lymphomas, defined in most studies as having ≥40% MYC+ and ≥50%-70% BCL2+ cells. DE large B-cell lymphomas are generally aggressive, although not as aggressive as DHL/THL, are more common than DHL/THL, and are more likely to have a nongerminal center phenotype. Whether single MYC rearrangements or MYC expression alone is of clinical importance is controversial. The field of the DHL/THL and DE large B-cell lymphomas is becoming more complex, with many issues left to resolve; however, great interest remains in identifying these cases while more is learned about them.
Elevated serum levels of IL-2R, IL-1RA, and CXCL9 are associated with a poor prognosis in follicular lymphoma
Authors: Mir Muhammad A. , Maurer Matthew J. , Ziesmer Steven C. , Slager Susan L. , Habermann Thomas , Macon William R. , Link Brian K. , Syrbu Sergei , Witzig Thomas , Friedberg Jonathan W. , Press Oliver , LeBlanc Michael , Cerhan James R. , Novak Anne , Ansell Stephen M. 
Published: November 2014

Key Points
Elevated IL-2R, IL-1RA, and CXCL9 are associated with shorter event-free survival in newly diagnosed FL, treated with chemoimmunotherapy. Increased serum IL-12 and IL-1RA is associated with shorter event-free survival in patients who were observed or treated with rituximab alone.
Healthcare-associated bloodstream infections in critically ill patients: descriptive cross-sectional database study evaluating concordance with clinical site isolates
Authors: Culshaw Nick , Glover Guy , Whiteley Craig , Rowland Katie , Wyncoll Duncan , Jones Andrew , Shankar-Hari Manu 
Published: November 2014

Abstract

Background
Healthcare-associated bloodstream infections are related to both increased antibiotic use and risk of adverse outcomes. An in-depth understanding of their epidemiology is essential to reduce occurrence and to improve outcomes by targeted prevention strategies. The objectives of the study were to determine the epidemiology, source and concordance of healthcare-associated bloodstream infections with clinical site isolates.

Methods
We conducted a descriptive cross-sectional study in critically ill adults admitted to a tertiary semi-closed intensive care unit in England to determine the epidemiology, source and concordance of healthcare-associated bloodstream infections with clinical site isolates. All nosocomial positive blood cultures over a 4-year study period were identified. Pathogens detected and concordances with clinical site are reported as proportions.

Results
Contaminant pathogens accounted for half of the isolates. The most common non-contaminant pathogens cultured were Pseudomonas spp. (8.0%), Enterococcus spp. (7.3%) and Escherichia coli (5.6%). Central venous catheter-linked bloodstream infections represent only 6.0% of the positive blood cultures. Excluding contaminants and central venous line infections, in only 39.5% of the bloodstream infections could a concordant clinical site source be identified, the respiratory and urinary tracts being the most common.

Conclusions
Clinical practice should focus on a) improving blood culture techniques to reduce detection of contaminant pathogens and b) ensuring paired clinical site cultures are performed alongside all blood cultures to better understand the epidemiology and potential implications of primary and secondary discordant health-care associated bloodstream infections.
Multiplex PCR performed of bronchoalveolar lavage fluid increases pathogen identification rate in critically ill patients with pneumonia: a pilot study
Authors: Baudel Jean-Luc , Tankovic Jacques , Dahoumane Redouane , Carrat Fabrice , Galbois Arnaud , Ait-Oufella Hafid , Offenstadt Georges , Guidet Bertrand , Maury Eric 
Published: November 2014

Abstract

Background
In critically ill patients with pneumonia, accurate microorganism identification allows appropriate antibiotic treatment. In patients undergoing bronchoalveolar lavage (BAL), direct examination of the fluid using Gram staining provides prompt information but pathogen identification accuracy is low. Culture of BAL fluid is actually the reference, but it is not available before 24 to 48 h. In addition, pathogen identification rate observed with direct examination and culture is decreased when antibiotic therapy has been given prior to sampling. We therefore assessed, in critically ill patients with suspected pneumonia, the performance of a multiplex PCR (MPCR) to identify pathogens in BAL fluid. This study is a prospective pilot observation.

Methods
We used a MPCR detecting 20 types of microorganisms. Direct examination, culture, and MPCR were performed on BAL fluid of critically ill patients with pneumonia suspicion. The final diagnosis of infective pneumonia was retained after the medical chart was reviewed by two experts. Pathogen identification rate of direct examination, culture, and MPCR in patients with confirmed pneumonia was compared.

Results
Among the 65 patients with pneumonia suspicion, the diagnosis of pneumonia was finally retained in 53 cases. Twenty nine (55%) were community-acquired pneumonia and 24 (45%) were hospital acquired. Pathogen identification rate with MPCR (66%) was greater than with culture (40%) and direct examination (23%) (p =0.01 and p <0.001, respectively). When considering only the microorganisms included in the MPCR panel, the pathogen identification rate provided by MPCR reached 82% and was still higher than with culture (35%, p <0.001) and direct examination (21%, p <0.001). Pathogen identification rate provided by MPCR was not modified in the case of previous antibiotic treatment (66% vs. 64%, NS) and was still better than with culture (23%, p <0.001).

Conclusions
The results of this pilot study suggest that in critically ill patients, MPCR performed on BAL fluid could provide higher identification rate of pathogens involved in pneumonia than direct examination and culture, especially in patients having received antimicrobial treatment.