bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence-Based Platelet Transfusion Guidelines
Authors: Slichter Sherrill J. 
Published: November 2007

AbstractTransfused platelets (plts) are either pooled random-donor platelet (plt) concentrates or single-donor apheresis plts. When stored for 5 days, all of these products are equally efficacious.A 10,000/μL prophylactic plt transfusion trigger has been documented to be both hemostatically efficacious and cost effective in reducing plt transfusion requirements. The optimal plt dose/transfusion is being evaluated in an ongoing clinical trial. Therapeutic plt transfusions to control or prevent bleeding with trauma or surgical procedures require higher transfusion triggers of 100,000/μL for neurosurgical procedures and between 50,000/μL and 100,000/μL for other invasive procedures or trauma.Leukoreduction has been documented to reduce plt alloimmunization rates, cytomegalovirus (CMV) transmission by transfusion, and febrile transfusion reactions. Whether it reduces immunomodulatory effects of transfusion (i.e., decreases infection rates and cancer recurrence) is still controversial, as is universal leukoreduction.Poor responses to plt transfusions are often multifactorial. For alloimmune plt refractoriness, HLA matching, cross-matching, and identification of the specificity of the patient’s antibodies with avoidance of mismatched donor antigens are all equally effective in identifying compatible plts for transfusion. Other causes of poor plt responses are splenomegaly, ABO mismatching, females with 2 or more pregnancies and males, use of heparin or amphotericin, bleeding, fever, graft-vs-host disease (GVHD), and vaso-occlusive disease (VOD).
Blood and Coagulation Support in Trauma Care
Authors: Hess John R. 
Published: November 2007

AbstractInjuries are common and account for almost 15% of all blood use in the U.S. The historic view that the coagulopathy associated with severe injury was largely dilutional is being replaced by epidemiologic and molecular evidence for a distinct syndrome of trauma-associated coagulopathy. This coagulopathy of trauma is the sum of the effects of blood loss and dilution, coagulation factor and platelet consumption, hypothermic platelet dysfunction and acidosis-induced decreases in coagulation factor activity, and fibrinolysis. Preventing the coagulopathy of trauma is best accomplished by preventing injury and hypothermia. Treating the coagulopathy of trauma requires its early recognition, prompt control of hemorrhage with local and systemic treatments, including in some patients the use of plasma instead of crystalloid solutions, and the prompt treatment of acidosis and hypothermia. The planned early use of allogenic plasma to treat many tens of thousands of massively transfused patients each year creates new demands for the immediate availability and improved safety of plasma products.
Risk, Cure and Complications in Advanced Hodgkin Disease
Authors: Horning Sandra J. 
Published: November 2007

AbstractCurrent therapy for Hodgkin disease is aimed at high cure rates and optimal survivorship. Although intensified chemotherapy with the escalated BEACOPP regimen resulted in higher rates of cure and survival compared with COPP/ABVD in the high-profile HD9 randomized controlled trial (RCT), this regimen has not been universally adopted by patients and physicians due to the attendant increased risks of early and late complications. Appropriately, questions emerge as to whether the results of this trial should be interpreted as establishing the superiority of BEACOPP over the current standard ABVD therapy, and whether clinical or biologic prognostic factors can better select patients for more intensive treatment. The widespread availability and high predictive accuracy of functional imaging with PET scans has led to promising, preliminary studies assessing early response to therapy with this diagnostic tool. In this review, the characteristics and outcomes of patients treated with ABVD in RCT will be made and compared with COPP/ABVD in HD9; clinical and biologic prognostic factors will be discussed, including PET imaging; and newer strategies targeted at minimizing treatment complications while maximizing cure rates will be discussed. Although enthusiasm for PET imaging is great, the challenges for using this diagnostic tool for risk-adapted therapies are substantial. Importantly, physicians and patients should be aware of these challenges, support the RCT that seek to address them, and carefully weigh risks and benefits for individual patients.
Clinical Features, Prognosis and Treatment of Follicular Lymphoma
Authors: Salles Gilles A. 
Published: November 2007

AbstractFollicular lymphoma constitutes the most frequent indolent lymphoma, well characterized by its clinical presentation related to nodal involvement and its morphologic and biologic features. Some rare locations of extranodal involvement, such as the gastrointestinal tract or skin, were recently further refined. The description of the Follicular Lymphoma International Prognostic Index (FLIPI) represents an important step in identifying patient subgroups with predictable outcome and comparing the results of clinical trials, although its use in clinical practice remains to be established. Analyses of gene expression profiles or constitutive gene variations may also provide additional insights for prognostication in the near future. Furthermore, these data underline the complex interactions between the tumor cells and their microenvironment; recent attempts to translate these findings with immunohistochemical studies remain unable to robustly predict patient outcome. The therapeutic strategies in follicular lymphoma have been transformed by monoclonal antibodies, used alone or in combination with chemotherapy. Treatment options should be adapted to the clinical features at diagnosis and appear to be able to modify the overall survival of some subgroups of patients. Further efforts may focus on strategies that can alter the natural history of this disease.
Mantle Cell Lymphoma: Identifying Novel Molecular Targets in Growth and Survival Pathways
Authors: O’Connor Owen A. 
Published: November 2007

Abstract
Mantle cell lymphoma (MCL) remains one of the more challenging sub-types of non-Hodgkin lymphoma. This entity, which is only approximately 10 years old, is characterized by response to many different chemotherapy regimens, though the duration of those responses remains often times quite short. Retreatment with second and third line combination regimens results in shorter and shorter durations of response, with the rapid emergence of a very drug-resistant phenotype. Despite these often frustrating clinical features, there is now a lot of new hope in managing patients with MCL. New insights into the molecular pathogenesis of MCL has revealed a plethora of new potential targets, while our continued efforts in novel targeted drug development has produced a host of agents that are already helping patients with this challenging disease. The use of proteasome inhibitors, for example, represents one example of a new strategy that has offered new hope for patients, and new opportunities for the physician treating this disease. In this review, we will put this biology into perspective, and describe how new revelations in MCL pathogenesis are leading to the identification of many exciting new drugs with promising activity.
Should Adolescents with NHL Be Treated as Old Children or Young Adults?
Authors: Sandlund John T. 
Published: November 2007

AbstractThe SEER (Surveillance, Epidemiology, and End Results) data for the years 1975–1998 show that children with non-Hodgkin lymphoma (NHL) have a better treatment outcome than do adults. Many factors may contribute to this age-related difference. Some factors are related to the patient (e.g., drug distribution and clearance, performance status, compliance, sex) whereas others pertain to tumor histology and biology. The spectrum of NHL subtypes is well known to differ in children and adults. From ages 5 through 14 years, Burkitt lymphoma is the predominant histologic subtype, whereas diffuse large B-cell lymphoma is most common in the 15- to 29-year age range. Because different treatment strategies are often used in children and adults with NHL, the choice of therapy for adolescents and young adults (ages 15 through 29 years) is challenging and somewhat controversial. It is reasonable to consider pediatric strategies for some adolescents and very young adults with NHL, and pediatric strategies are currently used to treat adults with certain subtypes of NHL (Burkitt lymphoma, lymphoblastic lymphoma). However, the use of pediatric strategies in adults does not guarantee a comparable outcome, as illustrated by trials for adult lymphoblastic lymphoma. There is clearly a need for further biologic study of NHL in children, adolescents, and young adults. Age-related differences in tumor biology have been demonstrated in anaplastic large-cell lymphoma (ALCL) and diffuse large B-cell lymphoma (DLBCL). Additional biologic data will not only improve prognosis and treatment stratification but, more important, will lead to the identification of specific molecular targets for therapy.
Strategies for Risk-Adapted Therapy in Myeloma
Authors: Fonseca Rafael 
Published: November 2007

AbstractIt is clear that the clinical heterogeneity of multiple myeloma (MM) is dictated, in large part, by disease biology, predominantly genetics.1 As novel therapeutics have emerged, and augmented our treatment armamentarium against the disease, it is increasingly important to introduce a risk-adapted approach for the optimal management of patients.2 The selection of ideal candidates for high-dose chemotherapy with stem cell support (HDT) and maintenance will undoubtedly have to include baseline knowledge of the genetic nature of the individual. The limited duration of responses after HDT for patients with t(4;14)(p16;q32), t(14;16)(q32;q23) and 17p13 deletions highlight the need to develop a risk-adapted treatment strategy.3–5 Novel ways of determining outcome such as the use of gene expression profiling have demonstrated differentiating capabilities not previously observed.6 Likewise, the order of introduction of novel therapeutic agents (during induction and in the relapsing patient) will be potentially directed by similar information. As we have previously stated, MM is not only multiple but also “many.”7 Accordingly, treatment strategies will be tailored based on risk determination, genetic composition and host features.
The Treatment of Relapsed and Refractory Multiple Myeloma
Authors: Richardson Paul , Mitsiades Constantine , Schlossman Robert , Ghobrial Irene , Hideshima Teru , Chauhan Dharminder , Munshi Nikhil , Anderson Kenneth 
Published: November 2007

AbstractRelapsed and refractory multiple myeloma (MM) constitutes a specific and unmet medical need. Median survival ranges from as little as 6 to 9 months, and responses to treatment are characteristically short. Patients with relapsed/refractory disease are defined as those who, having achieved minor response or better, relapse and then progress while on salvage therapy, or experience progression within 60 days of their last therapy. In the era prior to the development of novel biologically based therapies for MM, relapse from successive treatment regimens resulted in progressively shorter response durations, which typically reflected emerging drug resistance, as well as changes in disease biology within each patient, with tumor cells expressing a more aggressive phenotype, higher proliferative fraction and lower apoptotic rates.Both bortezomid- and lenalidomide-based therapies are expecially active, with bortezomib in particular being shown to provide a platform for combinations able to overcome resistance in this setting. The addition of novel and conventional agents to the treatment backbone of lenalidomide, thalidomide, and bortezomib are areas of active study, with participation in clincial trials a clear priority for such patients. Clinical challenges in the relapsed/refractory population include light chain and IgA isotype, renal failure, extramedullary disease, hyposecretory myeloma, and advanced bone disease.
Familial CLL: Genes and Environment
Authors: Goldin Lynn R. , Slager Susan L. 
Published: November 2007

AbstractFamilies with multiple individuals affected with chronic lymphocytic leukemia (CLL) and other related B-cell tumors have been described in the literature. Familial CLL does not appear to differ from sporadic CLL in terms of prognostic markers and clinical outcome. While some environmental factors (such as farming-related exposures and occupational chemicals) may increase risk of CLL, results of epidemiologic studies have been generally inconsistent. Rates of CLL in the population show significant international variation, with the highest rates in the U.S. and Europe and the lowest rates in Asia. Migrants from Asia to the U.S. also have low rates of CLL, which supports a greater role for genetic compared with environmental risk factors. Large, population-based case-control and cohort studies have also shown significant familial aggregation of CLL and related conditions including non-Hodgkin and Hodgkin lymphoma. Monoclonal B-cell lymphocytosis also aggregates in families with CLL. However, the clinical implication of familial aggregation is minimal given the overall rarity of CLL. Linkage studies have been conducted in high-risk CLL families to screen the whole genome for loci that contribute to susceptibility, but no gene mutations have yet been identified by this method. Association studies of candidate genes have implicated immune function and other genes, but more studies are needed to verify these findings. The ability to conduct large-scale genomic studies will play an important role in detecting susceptibility genes for CLL over the next few years and thereby help to delineate etiologic pathways.
Biology and Treatment of Primary Myelofibrosis
Authors: Hoffman Ronald , Rondelli Damiano 
Published: November 2007

Abstract
Primary myelofibrosis (PMF) is a chronic myeloproliferative disorder associated with an average survival of less than 5 years. Therapy for PMF has used chemotherapeutic agents, immunomodulatory drugs, or biological-response modifiers that have not always been directed at the biological processes that underlie the origins of PMF. Such strategies are palliative and have an uncertain effect on survival. At present, allogeneic stem cell transplantation (ASCT) is the only means of altering the natural history of patients with PMF and provides the only hope for cure of this disorder. Enthusiasm for ASCT in PMF has been muted due to an unacceptable transplantation-related morbidity and mortality in patients receiving fully myeloablative conditioning regimens. Recently, a variety of reduced-intensity conditioning regimens have been utilized in older patients with PMF with significant comorbidities with promising results. Greater understanding of the cellular and molecular events that lead to the development of PMF have provided the opportunity for targeted therapies for PMF. Such therapies must be first evaluated in phase 1/2 trials using a variety of endpoints to assess their efficacy and their potential associated toxicities. The performance of randomized clinical trials comparing these agents to the present standard of care would permit for the first time evidence-based therapeutic decisions to be made for patients with PMF.
Implication of the Molecular Characterization of Acute Myeloid Leukemia
Authors: Döhner Hartmut 
Published: November 2007

AbstractThe identification of molecular genetic alterations such as gene mutations or deregulated gene expression in acute myeloid leukemia (AML) has greatly advanced our understanding of leukemogenesis. These markers now allow us to unravel the enormous heterogeneity seen within cytogenetically defined subgroups of AML. Furthermore, the molecular alterations are providing targets for molecular therapies. In this article, major molecular findings of prognostic and predictive significance are reviewed, with an emphasis on the discussion of gene mutations found in two major AML subgroups, cytogenetically normal and core-binding factor AML.
Prognostic Factors in Elderly Patients with AML and the Implications for Treatment
Authors: Erba Harry P. 
Published: November 2007

AbstractThe outcome of older patients with acute myeloid leukemia (AML) has not improved in the last three decades. These patients are more likely to have comorbid illness, poor performance status, and impaired organ function. These clinical features limit their ability to tolerate intensive cytotoxic chemotherapy and result in greater early mortality. The AML seen in elderly patients is also more likely to have evolved from a prior hematologic disorder, and the leukemic blasts are more likely to have poor-risk structural and numeric cytogenetic abnormalities and expression of multidrug resistance protein (MDR1). These blast features have been associated with greater resistance to therapy. Attempts to improve outcome have generally been unsuccessful. Priming of leukemic blasts with granulocyte colony-stimulating factors during cytarabine therapy, granulocyte colony-stimulating factor support to speed neutrophil recovery following induction therapy, inhibition of the MDR1 p-glycoprotein efflux pump, the use of alternative anthracyclines, and the addition of high-dose cytarabine have all been investigated in the last three decades. Further manipulation of standard cytotoxic chemotherapy alone is unlikely to improve the outcome for the majority of patients with AML. Incorporation of molecularly targeted therapies may prove to be less toxic and/or more efficacious. However, patient selection for clinical trials will continue to confound the interpretation of treatment outcomes on clinical trials of older patients with AML.
Update on Progress and Hurdles in Novel Genetic Therapies for Hemophilia
Authors: High Katherine A. 
Published: November 2007

Abstract
Among inherited disorders, hemophilia has a number of characteristics that make it attractive as a model for gene transfer approaches. Several trials of gene therapy for hemophilia were carried out earlier in this decade; these trials were all first-in-class, i.e. the first use of a particular vector system in a particular target tissue, and thus yielded important safety data for the approaches under investigation. None, however, resulted in long-term expression of the clotting factor at therapeutic levels, and each encountered a critical issue, either in terms of safety, efficacy, or feasibility, that required further laboratory or clinical investigation. Ongoing trials of gene transfer for hemophilia include AAV-mediated gene transfer to liver using modified vectors (alternate serotypes, self-complementary constructs) or adjuvant therapies (transient immunosuppression). Preclinical studies using lentiviral vectors to transduce liver or hematopoietic cells have been promising, and genome editing and translational bypass strategies are also being investigated. Challenges to successful development of each strategy will be discussed.
Membrane Lipid Alterations in Hemoglobinopathies
Authors: Kuypers Frans A. 
Published: November 2007

AbstractThe red blood cell (RBC) membrane is a complex mixture of lipids and proteins. Hundreds of phospholipid molecular species spontaneously arrange themselves in a lipid bilayer and move rapidly in the plane as well as across the bilayer in a dynamic but highly organized fashion. Areas enriched in certain lipids determine proper protein function. Phospholipids are asymmetrically distributed across the lipid bilayer with phosphatidylserine (PS) exclusively on the inside. Both the composition and organization of the RBC membrane is well maintained. Alterations lead to apoptosis during erythropoiesis or early demise of the cell in the circulation. The mechanisms that govern the maintenance of the lipid bilayer are only recently being unraveled at the individual protein level. Oxidized lipids are rapidly repaired using fatty acids taken up from plasma to maintain membrane integrity. Several isoforms of a RBC acyl-Coenzyme A (CoA) synthase have been reported, as well as the first member of a family of lysophospholipid acylCoA acyltransferases. Phospholipid asymmetry is maintained by the recently identified RBC amino-phospholipid translocase. These enzymes, essential in maintaining membrane lipid organization, are affected by oxidant stress or an increase in cytosolic calcium. Normal lipid composition and organization is lost in subpopulations of RBC in hemoglobinopathies such as sickle cell disease and thalassemia. Despite elaborate antioxidant systems, lipids and membrane proteins, including those that maintain lipid organization, are damaged in these cells. This in turn leads to improper repair of damaged RBC membranes and altered interactions of RBCs with other blood cells and plasma components that play a role in the pathology that defines these disorders. The altered lipid bilayer in RBCs in hemoglobinopathies leads to premature removal (anemia) and imbalance in hemostasis, and plays a role in vaso-occlusive crisis in sickle cell disease. Lipid breakdown products of PS-exposing cells result in vascular dysfunction, including acute chest syndrome in sickle cell disease. In summary, altered membrane lipids play an important role in the pathology of hemoglobinopathies and characterization of the proteins involved in lipid turnover will elucidate the pathways that maintain plasma membrane organization and cellular viability.
Hypercoagulability in Sickle Cell Disease: New Approaches to an Old Problem
Authors: Ataga Kenneth I. , Key Nigel S. 
Published: November 2007

AbstractPatients with sickle cell disease (SCD) exhibit high plasma levels of markers of thrombin generation, depletion of natural anticoagulant proteins, abnormal activation of the fibrinolytic system, and increased tissue factor expression, even in the non-crisis steady state. In addition, platelets and other cellular elements are chronically activated in the non-crisis state. Despite an abundance of evidence for coagulation and platelet activation, it remains uncertain whether these changes contribute to the pathophysiology of SCD or are, rather, simple epiphenomena. With the occurrence of macrovascular thrombotic complications in SCD, as well as the recognition that soluble CD40 ligand is biologically active in SCD, coagulation and platelet activation may indeed play a role in SCD pathophysiology. Defining a role for hypercoagulability in SCD requires further understanding of its pathogenesis. Furthermore, the conduct of well-controlled clinical trials using anticoagulants and antiplatelet agents and using a variety of clinical endpoints is warranted.