bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sickle-Cell Trait: Novel Clinical Significance
Authors: Key Nigel S. , Derebail Vimal K. 
Published: January 2011

AbstractThere is a long-standing controversy in the literature as to whether sickle-cell trait (SCT) should be viewed as a benign carrier state or as an intermediate disease phenotype. Because SCT is routinely detected by neonatal screening for sickle-cell disease, it becomes imperative that consensus on this issue be achieved in order to provide the best medical advice to affected individuals. The issue of selective screening in the post-neonatal period was thrust into the limelight recently by the National Collegiate Athletic Association's recommendation that its member colleges and universities test student-athletes to confirm their carrier status if not already known. The stated goal of this recommendation was to prevent exercise-related sudden death in athletes with SCT. We review some of the reported complications of SCT for which new information has emerged, focusing particularly on venous thromboembolism and renal manifestations.
Dealing with Neuropathy in Plasma-Cell Dyscrasias
Authors: Sonneveld Pieter , Jongen Joost L.M. 
Published: January 2011

AbstractPeripheral neuropathy (PN) is a frequent complication of plasma-cell dyscrasias such as monoclonal gammopathy of undetermined significance, multiple myeloma, Waldenström's disease, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome, Castleman's disease, and light-chain amyloidosis. PN can be associated with the underlying disease or it can related to the treatment. The novel immunomodulatory drugs thalidomide and lenalidomide and the proteasome inhibitor bortezomib have changed the standard treatment of multiple myeloma. Treatment-related PN induced by thalidomide (TiPN) or bortezomib (BiPN) has become the most frequent cause of symptomatic polyneuropathy in multiple myeloma and related diseases. Dealing with PN has become a major challenge in current clinical practice for multiple myeloma patients. This review deals with practical issues such as etiology, incidence, symptoms, and clinical management of treatment-emergent PN. The major focus of the hematologist should be on the prevention of PN, primarily by frequent monitoring of the patient and by timely and adequate dose reduction of thalidomide and bortezomib. Thalidomide should not be given for periods longer than 18 months, and if it is, then patients should be carefully monitored with a low threshold for discontinuation in the face of any emergent neuropathy. In the case of BiPN, the dose of bortezomib should be reduced and/or the administration interval should be prolonged from biweekly to weekly. Adequate pain management and supportive care require a multidisciplinary approach involving the treating physician, expert nursing staff, and a neurologist as clinically indicated.
Alternative Donor Transplantation for Aplastic Anemia
Authors: Eapen Mary , Horowitz Mary M. 
Published: January 2011

AbstractPatients with severe aplastic anemia who do not have a human leukocyte antigen (HLA)-identical sibling generally receive immunosuppressive therapy as a first-line therapy, with allogeneic transplantation being reserved for those who do not have an adequate sustained response. Barriers to the use of unrelated-donor transplantation for aplastic anemia include identifying a suitable alternative donor, and risks of graft failure, regimen-related toxicity, and graft-versus-host disease (GVHD). Despite the more than 14 million adults registered with donor registries worldwide, only approximately 50% of patients of Caucasian descent will have an available and fully HLA-matched unrelated adult donor; the rate is substantially lower for non-Caucasians. While umbilical cord blood allows transplantation with greater donor-recipient HLA disparity (without excessive risk of GVHD), risks of graft failure and transplant-related mortality are higher than after transplantation of adult donor grafts. Among patients with a suitable donor, recent changes in pre-transplant conditioning regimens have lowered the risks of organ toxicity and graft failure. Although advances in donor HLA typing and selection practices and improved GVHD prophylaxis have lowered the risk, GVHD remains an important obstacle to long-term symptom-free survival. Despite these limitations, unrelated-donor transplantation offers the best chance of long-term survival for many patients in whom current immunosuppression strategies are not effective. Wider applicability of alternative-donor transplantation for aplastic anemia will require better approaches to prevent graft failure and GVHD and to expand the pool of unrelated-donor grafts. This includes exploring strategies to effectively use alternative grafts such as umbilical cord blood.
Renal Insufficiency and Failure
Authors: Dimopoulos Meletios A. , Terpos Evangelos 
Published: January 2011

Abstract
Renal impairment is a common complication of multiple myeloma. Chronic renal failure is classified according to glomerular filtration rate as estimated by the MDRD (modification of diet in renal disease) formula, while RIFLE (risk, injury, failure, loss and end-stage renal disease) and AKIN (acute renal injury network) criteria may be used for the definition of the severity of acute renal injury. Novel criteria based on estimated glomerular filtration rate measurements are proposed for the definition of the reversibility of renal impairment. Renal complete response (CRrenal) is defined as sustained (i.e., lasting at least 2 months) improvement of creatinine clearance (CRCL) from under 50 mL/min at baseline to 60 mL/min or above. Renal partial response (PRrenal) is defined as sustained improvement of CRCL from under 15 mL/min at baseline to 30 to 59 mL/min. Renal minor response (MRrenal) is defined as sustained improvement of the baseline CRCL of under 15 mL/min to 15 to 29 mL/min or, if baseline CRCL was 15 to 29 mL/min, improvement to 30 to 59 mL/min. Bortezomib with high-dose dexamethasone is considered the treatment of choice for myeloma patients with renal impairment and improves renal function in most patients. Although there is limited experience with thalidomide, this agent can be administered at the standard dosage to patients with renal failure. Lenalidomide, when administered at reduced doses according to renal function, is effective and can reverse renal impairment in a subset of myeloma patients.
Thrombosis in Multiple Myeloma
Authors: Kristinsson Sigurdur Yngvi 
Published: January 2011

AbstractPatients with multiple myeloma (MM) are at an increased risk of venous and arterial thrombosis. The pathogenesis remains unclear, but probably involves several factors such as activation of procoagulant factors, acquired activated protein C resistance, and inflammation. In addition to general risk factors for venous thromboembolism, such as older age, immobility, surgery, and inherited thrombophilia, there are some MM-specific and treatment-related factors that contribute to the increased risk. The risk for venous thromboembolism is high when patients are treated with thalidomide or lenalidomide in combination with dexamethasone or multi-agent chemotherapy. Thromboprophylaxis should be given in these settings. Which agent is the most appropriate is a matter of debate, but aspirin, low-molecular-weight heparin, and warfarin all seem to be effective. This review discusses risk factors for thromboembolism in MM and general, disease-specific and treatment-related mechanisms for thrombosis. Recommendations for thromboprophylaxis are described and treatment choices for venous thrombosis in MM patients are reviewed.
Genetic Therapy for Beta-Thalassemia: From the Bench to the Bedside
Authors: Arumugam Paritha , Malik Punam 
Published: January 2011

AbstractBeta-thalassemia is a genetic disorder with mutations in the β-globin gene that reduce or abolish β-globin protein production. Patients with β-thalassemia major (Cooley's anemia) become severely anemic by 6 to 18 months of age, and are transfusion dependent for life, while those with thalassemia intermedia, a less-severe form of thalassemia, are intermittently or rarely transfused. An allogeneically matched bone marrow transplant is curative, although it is restricted to those with matched donors. Gene therapy holds the promise of “fixing” one's own bone marrow cells by transferring the normal β-globin or γ-globin gene into hematopoietic stem cells (HSCs) to permanently produce normal red blood cells. Requirements for effective gene transfer for the treatment of β-thalassemia are regulated, erythroid-specific, consistent, and high-level β-globin or γ-globin expression. Gamma retroviral vectors have had great success with immune-deficiency disorders, but due to vector-associated limitations, they have limited utility in hemoglobinopathies. Lentivirus vectors, on the other hand, have now been shown in several studies to correct mouse and animal models of thalassemia. The immediate challenges of the field as it moves toward clinical trials are to optimize gene transfer and engraftment of a high proportion of genetically modified HSCs and to minimize the adverse consequences that can result from random integration of vectors into the genome by improving current vector design or developing novel vectors. This article discusses the current state of the art in gene therapy for β-thalassemia and some of the challenges it faces in human trials.
Update on Iron Chelators in Thalassemia
Authors: Neufeld Ellis J. 
Published: January 2011

AbstractOver the past four decades, there have been dramatic improvements in survival for patients with thalassemia major due in large measure to improved iron chelators. Two chelators are approved for use in the United States and Canada, parenteral deferoxamine and oral deferasirox. Three are available in much of the rest of the world, where oral deferiprone is also approved (in the United States, deferiprone is only available in studies, for emergency use, or on a “compassionate-use” basis). Many trials and worldwide clinical experience demonstrate that each of the three drugs can chelate and remove iron, and thereby prevent or improve transfusional hemosiderosis in thalassemia patients. However, the chelators differ strikingly in side-effect profile, cost, tolerability and ease of adherence, and (to some degree) efficacy for any specific patient. The entire field of chelator clinical trials suffers from the fact that each drug (as monotherapy or in combination) has not been tested directly against all of the other possibilities. Acknowledging the challenges of assessing chelators with diverse properties and imperfect comparative data, the purpose of this review is to summarize the last 4 years of studies that have improved our understanding of the applications and limitations of iron chelators in various settings for thalassemia patients, and to point out areas for much-needed future research.
Hematopoietic Stem Cell Transplantation in Thalassemia
Authors: Angelucci Emanuele 
Published: January 2011

AbstractAlmost 30 years have passed since the first successful hematopoietic stem cell transplantation in thalassemia and that first patient is now a healthy young adult with a completely normal life. Since that time, more than 3000 such transplants have been performed worldwide. This review provides a brief history of hematopoietic stem cell transplantation in thalassemia and reassesses current clinical results with the objective to provide outcome predictions based on modern transplant technologies. The role of hematopoietic stem cell transplantation in the oral chelation era and implications for possible closure in the approach to future gene therapy will also be discussed.
Trauma Blood Management: Avoiding the Collateral Damage of Trauma Resuscitation Protocols
Authors: Hannon Timothy 
Published: January 2011

Abstract
The use of high ratios of red blood cells to platelets and plasma in trauma resuscitation protocols is quickly gaining favor in civilian trauma centers. The use of higher ratios of coagulation factors to red blood cells has been shown to improve outcomes in both military and civilian centers, but does the evidence support the use of a 1:1:1 ratio, as has been suggested? There is growing evidence that the use of such high ratios may be excessive and potentially harmful, and there has not been enough emphasis on the other components of evidence-based “damage control” resuscitation.
Optimal Use of Blood Products in Severely Injured Trauma Patients
Authors: Holcomb John B. 
Published: January 2011

AbstractInjury is the leading cause of life years lost in the United States, and uncontrolled hemorrhage is the leading cause of potentially preventable death. Traditionally, these patients have been serially resuscitated with large volumes of crystalloid and/or colloids and red blood cells, followed by smaller amounts of plasma and platelets. Transfusion data coming first from the ongoing war in Iraq and Afghanistan and followed by multiple civilian studies have brought into question this tradition-based practice. Numerous recent retrospective single and multicenter studies have associated improved outcomes with earlier and increased use of plasma and platelets. These data have stimulated significant interest in studying massively transfused trauma patients. Most clinicians have concluded that the optimal timing and quantity of blood products in the treatment of hypothermic, coagulopathic, and acidotic trauma patients are unclear. Although there are strongly held opinions and long-standing traditions in their use, there are little quality data within which to logically guide resuscitation therapy. A multicenter prospective observational study is ongoing, and randomized trials are planned. This review will address the issues raised previously and describe recent trauma patient outcome data utilizing predetermined plasma:platelet:red blood cell transfusion ratios, and possibilities for future transfusion products and research.
New Prognostic Markers in Acute Myeloid Leukemia: Perspective from the Clinic
Authors: Foran James M. 
Published: January 2011

Abstract
Acute myeloid leukemia (AML) is a disease with marked heterogeneity in both response to therapy and survival. Cytogenetics, age, and performance status have long determined prognosis and therapy. The advent of molecular diagnostics has heralded an explosion in new prognostic factors, including gene mutations in KIT, FLT3 (Fms-like tyrosine kinase 3), NPM1 (nucleophosmin 1), and CEBPA (CCAAT enhancer-binding protein-α). Microarray technology can now identify unique gene expression signatures associated with prognosis. Similarly microRNA expression, single nucleotide polymorphism arrays, and DNA methylation signatures have recently described important new prognostic subgroups of AML, and are contributing to our understanding of AML disease biology. Combined with proteomic profiling, these technologies have helped identify new targets and signaling pathways, and may soon help to identify individual patients likely to benefit from specific therapies, including allogeneic hematopoietic cell transplantation. In summary, new clinical and molecular prognostic markers have begun to significantly improve our understanding of AML biology. We are now close to a time when we will be able to use these prognostic factors and technologies to identify new targets for therapy and to determine who may benefit from that therapy, and ultimately change how we treat individual patients with AML.
High Cytogenetic or Molecular Genetic Risk Acute Myeloid Leukemia
Authors: Estey Elihu 
Published: January 2011

Abstract
Resistance, manifested as failure to enter remission despite living long enough to do so or as relapse from remission, is the principal cause of therapeutic failure in acute myeloid leukemia, even in patients age ≥ 75. Recently, a “monosomal karyotype” in acute myeloid leukemia blasts has been found to be a principal predictor of resistance. It is also clear that patients with a normal karyotype, and other intermediate prognosis karyotypes, can be placed into a high-risk group based on the absence of a mutation in the NPM1 gene or the presence of an internal tandem duplication (ITD) of the Fms-like tyrosine kinase 3 gene (FLT3) gene, particularly if there is loss of the wild-type FLT3 allele. The effects of other genetic abnormalities have been inconsistent, perhaps reflecting differences in expression of the abnormality and its translation into protein. Several reports have shown the prognostic potential of profiling global gene expression, micro-RNA expression, DNA methylation, and proteomics. Although routine application of these approaches is still premature, pretreatment assessment of the nucleophosmin 1 (NPM1) mutation and FLT3 ITD status, as well as cytogenetics, should be routine. These results can be used to guide the choice of remission induction therapy, for example, by placing patients with monosomal karyotype or FLT3 ITDs on clinical trials. Allogeneic hematopoietic cell transplant in first complete remission is generally indicated for high-risk patients. However, new approaches are needed to reduce the high rates of relapse, even after hematopoietic cell transplant.
Understanding and Managing Ultra High-Risk Chronic Lymphocytic Leukemia
Authors: Stilgenbauer Stephan , Zenz Thorsten 
Published: January 2011

AbstractModern treatment approaches such as chemoimmunotherapy (e.g., fludarabine/cyclophosphamide/rituximab or FCR) are highly effective in the majority of chronic lymphocytic leukemia (CLL) patients. However, there remains a small but challenging subgroup of patients who show ultra high-risk genetics (17p deletion, TP53 mutation) and/or poor response to chemoimmunotherapy. The median life expectancy of these patients is below 2 to 3 years with standard regimens. Accordingly, CLL with the 17p deletion (and likely also with sole TP53 mutation) should be treated with alternative strategies. While p53 defects appear to play a central role in our understanding of this ultra high-risk group, at least half of the cases will not be predictable based on existing prognostic models. Current treatment approaches for patients with p53 defects or poor response to chemoimmunotherapy should rely on agents acting independently of p53, such as alemtuzumab, lenalidomide, flavopiridol, and a growing number of novel compounds (or combinations thereof) currently available in clinical trials. Poor survival times of patients with ultra high-risk CLL suggest that eligible patients should be offered consolidation with reduced-intensity allogeneic stem-cell transplantation or experimental approaches in clinical trials.
Ultra High-Risk Myeloma
Authors: Avet-Loiseau Hervé 
Published: January 2011

Abstract
Ultra high-risk myeloma can be defined as myeloma leading to death within 24 months. Despite tremendous improvements in the past decade (especially because of the availability of novel drugs such as thalidomide, bortezomib, and lenalidomide), these patients still represent 15% to 20% of the patients. Many prognostic factors can help to define these patients, including age, renal insufficiency, poor performance status, comorbities, International Staging System (ISS) stage 3, high proliferation, leukemic presentation, and acquired genetic changes, as defined by interphase fluorescence in situ hybridization or genomics. Several combinations of these prognostic parameters can define ultra high-risk patients, making a universal therapeutic proposal almost impossible. However, focusing on fit patients with ISS 3, high proliferation, and poor-risk genetic changes, these patients should probably benefit from dose-dense and prolonged therapeutic schemas, ideally within prospective trials.
New Trends in the Standard of Care for Initial Therapy of Acute Myeloid Leukemia
Authors: Fernandez Hugo F. 
Published: January 2011

AbstractIn younger patients with acute myeloid leukemia (AML), initial treatment has provided very good control of the disease. Induction therapy has used combination chemotherapy, with anthracycline and cytarabine as the foundation. Recent trials support dose intensification of anthracycline in induction. Intensive postremission therapy further contributes to improving survival. The addition of targeted therapy with gemtuzumab ozogamicin to standard therapy has not improved on these outcomes. Newer agents targeted to specific molecular abnormalities or survival mechanisms in the leukemic cell are being studied as future additions to the current standard therapy.
Treating the Elderly Patient with Acute Myelogenous Leukemia
Authors: Luger Selina M. 
Published: January 2011

Abstract
Decisions regarding the optimal treatment of acute myelogenous leukemia in the elderly patient requires the consideration of multiple factors. Population-based studies have demonstrated that, for all age groups, aggressive therapy results in improved survival and quality of life when compared with palliative care. The optimal induction and postremission regimen for older patients has yet to be determined. Furthermore, not all patients are candidates for such therapy. Consideration of patient and disease-related factors can help to determine the appropriateness of intensive therapy in a given patient. For those patients for whom aggressive induction therapy does not seem to be in their best interest, novel agents are being investigated that will hopefully address the issues of induction death and early relapse associated with these patient populations.
Minimal Residual Disease in Acute Lymphoblastic Leukemia
Authors: Campana Dario 
Published: January 2011

AbstractIn patients with acute lymphoblastic leukemia (ALL), treatment response is increasingly evaluated with minimal residual disease (MRD) assays. ALL cells can be recognized by their clonal rearrangement of immunoglobulin and T-cell receptor genes, expression of gene fusions, and leukemia-associated immunophenotypes. Assays based on polymerase chain reaction or flow cytometry can detect one ALL cell among 10,000 to 100,000 normal cells in clinical samples. The vast majority of cases have antigen-receptor gene rearrangements and leukemia immunophenotypes for MRD monitoring; about half of the cases currently have suitable gene fusions. The clinical significance of MRD has been conclusively demonstrated in both childhood and adult ALL. In most studies, MRD positivity is defined by the presence of 0.01% or more ALL cells; the risk of relapse is generally proportional to the level of MRD, particularly when measured during or at the end of remission-induction therapy. The prevalence of MRD during early therapy differs among genetic and biologic ALL subtypes. However, being a measurement of drug resistance in vivo and reflecting multiple cellular, host, and treatment variables, MRD is typically an independent prognostic factor. MRD is now used in several clinical trials for risk assignment and to guide clinical management overall. The time points at which MRD testing is performed and the threshold levels that trigger treatment intensification vary according to the methodology available, the results of preclinical correlative studies, and protocol design.