bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hematopoietic Stem Cell Transplantation for Sickle Cell Disease: Current Practice and Emerging Trends
Authors: Shenoy Shalini 
Published: December 2011

AbstractAllogeneic HSCT controls sickle cell disease (SCD)–related organ damage and is currently the only curative therapy available. Over the last 2 decades, HSCT has been limited largely to myeloablative matched sibling donor (MSD) procedures that are feasible only in a minority of patients. As the natural history of the disease has evolved, it is clear that subsets of patients with severe disease are at risk for sudden death, devastating CNS and pulmonary complications, and debilitating vasoocclusive crises. For these patients, the benefits of transplantation can outweigh the risks if HSCT can be safely and successfully performed with low early and late toxicities. This review describes advances and ongoing investigation of HSCT for SCD from the perspectives of recipient age and presentation, donor stem cell source, intensity of conditioning, family and medical perspectives, and other variables that influence outcome. Ultimately, HSCT should be viewed as a viable treatment option for SCD on par with other therapies for select patients who can benefit from the procedure.
Stem Cell Transplantation in Inherited Metabolic Disorders
Authors: Wynn Robert 
Published: December 2011

Abstract
Allogeneic HSCT is performed for a small number of inborn errors of metabolism (IEM). Over the last years, transplantation outcomes have improved in this group of patients as the factors that predicted for poor transplantation outcomes were understood and addressed. The role of transplantation and its potential benefit for an individual patient with a certain IEM is therefore now much better defined. In parallel with improvements in transplantation techniques, other therapies such as pharmacological enzyme replacement therapy (ERT), substrate inhibition, and gene therapy have been developed and are increasingly available to clinicians and their patients. This review covers the following areas: (1) the scientific principles that underpin transplantation in IEM; (2) the variables of the transplantation process itself that predict for successful outcome in terms of engrafted survival after HSCT; (3) the reasons that some apparently phenotypically similar disorders might respond very differently to transplantation therapy; (4) the factors that currently influence the response of a particular patient with a particular disease to allogeneic transplantation, and how these factors might be manipulated in the future to further improve transplantation outcomes in different metabolic illnesses; and (5) how other therapeutic modalities, including ERT, gene therapy, and substrate reduction therapy, might complement and compete with HSCT in the coming years.
Complications, Diagnosis, Management, and Prevention of CMV Infections: Current and Future
Authors: Boeckh Michael 
Published: December 2011

Abstract
Although major progress has been made in the prevention of CMV disease after hematopoietic cell transplantation (HCT), specific problems remain and available antiviral agents are associated with major toxicities. This article reviews current aspects of CMV diagnosis, prevention, and treatment in HCT recipients and defines areas of unmet medical need.
Optimal Therapy of Advanced Hodgkin Lymphoma
Authors: Advani Ranjana 
Published: December 2011

AbstractAdvanced-stage Hodgkin lymphoma (HL) has become a curable disease in the majority of patients. Research during the last decade has challenged chemotherapy with Adriamycin, bleomycin, vinblastine, dacarbazine (ABVD) as the standard of care and debates continue regarding the role of radiation therapy (RT) in this patient population. The incorporation of interim positron emission tomography (PET) imaging and, recently, further characterization of HL on cellular and molecular levels are emerging as tools for treatment stratification and predictors of disease status. Newer targeted therapies have emerged that are very effective in the relapsed setting and are actively being explored as frontline therapy. Lastly, the expanding population of survivors cured of HL outnumbers patients with the disease and needs to be monitored for therapy-related late effects.
Late Effects in the Era of Modern Therapy for Hodgkin Lymphoma
Authors: Hodgson David C. 
Published: December 2011

Abstract
Extended-field and subtotal nodal radiation therapy (RT), developed in the 1960s, was the first reliably curative treatment for early-stage Hodgkin lymphoma (HL). However, the large volume of normal tissue irradiated resulted in significant delayed toxicity, including cardiac disease and second cancers (SCs). The 30-year cumulative incidence of heart disease among adult survivors receiving 40-45 Gy of extended-field or mantle RT is approximately 30%; the incidence of SCs is similar. Improving disease control while reducing the toxicity of treatment has been a major objective of HL trials for more than 2 decades. Contemporary involved-field RT (IFRT) reduces irradiated volumes and produces significant reductions in normal tissue dose compared with historic treatments. Recent data indicate that, compared with mantle RT, IFRT reduces the relative risk of breast cancer among young females receiving mediastinal RT by approximately 60% and also reduces cardiac dose. The recent transition to involved-node RT allows further reductions in normal tissue dose. Response-adapted therapy is being evaluated in clinical trials as a means of identifying those patients most likely to benefit from treatment reduction or intensification, enhanced screening will facilitate early intervention to reduce the clinical burden of late effects, and there is increasing interest in elucidating the genetic correlates of treatment toxicity.
B Cells Behaving Badly: A Better Basis to Behold Belligerence in B-Cell Lymphomas
Authors: Bagg Adam 
Published: December 2011

AbstractA plethora of genetic abnormalities has been described in B-cell lymphomas, some of which arise when physiologic mechanisms involved in the generation of immunologic diversity go awry. Several different lymphoma types, such as follicular lymphoma (FL), mantle cell lymphoma (MCL), and Burkitt lymphoma (BL), are associated with hallmark translocations that occur as a consequence of these errors (t(14;18)(q32;q21), t(11;14)(q13;q32), and t(8;14)(q24;q32), respectively); however, none of these associations is absolute and none is completely diagnostically specific or sensitive. The advantages and limitations of a variety of different testing strategies in the 2 most common lymphomas, FL and diffuse large B-cell lymphoma (DLBCL), are reviewed herein, including an evaluation of the role of PCR-based approaches, FISH, and more nascent genomic technologies. The use of immunophenotypic strategies that may potentially provide, albeit imperfectly, more user-friendly surrogates for underlying genetic aberrations and cell-of-origin designations derived from gene-expression profiling analyses are also discussed. Finally, a newly designated category of lymphoma with features intermediate between DLBCL and BL is appraised, highlighting the central role of genetic analysis in this diagnostic gray zone.
Many Multiple Myelomas: Making More of the Molecular Mayhem
Authors: Chesi Marta , Bergsagel P. Leif 
Published: December 2011

Abstract
Multiple myeloma (MM) is malignancy of isotype-switched, BM-localized plasma cells that frequently results in bone destruction, BM failure, and death. Important molecular subgroups are identified by three classes of recurrent immunoglobulin gene translocations and hyperdiploidy, both of which affect disease course. From a clinical standpoint, it is critical to identify MM patients carrying the t(4;14) translocation, which is present in 15% of myelomas and is associated with dysregulation of WHSC1/MMSET and often FGFR3. These patients should all receive bortezomib as part of their initial induction treatment because this has been shown to significantly prolong survival. In contrast, patients with translocations affecting the MAF family of transcription factors, del17p, or gene-expression profiling (GEP)–defined high-risk disease appear to have a worse prognosis that is not dramatically improved by any intervention. These patients should be enrolled in innovative clinical trials. The remaining patients with cyclin D translocations or hyperdiploidy do well with most therapies, and the goal should be to control disease while minimizing toxicity.
Impact of Genetic Features on Treatment Decisions in AML
Authors: Döhner Hartmut , Gaidzik Verena I. 
Published: December 2011

AbstractIn recent years, research in molecular genetics has been instrumental in deciphering the molecular pathogenesis of acute myeloid leukemia (AML). With the advent of the novel genomics technologies such as next-generation sequencing, it is expected that virtually all genetic lesions in AML will soon be identified. Gene mutations or deregulated expression of genes or sets of genes now allow us to explore the enormous diversity among cytogenetically defined subsets of AML, in particular the large subset of cytogenetically normal AML. Nonetheless, there are several challenges, such as discriminating driver from passenger mutations, evaluating the prognostic and predictive value of a specific mutation in the concert of the various concurrent mutations, or translating findings from molecular disease pathogenesis into novel therapies. Progress is unlikely to be fast in developing molecular targeted therapies. Contrary to the initial assumption, the development of molecular targeted therapies is slow and the various reports of promising new compounds will need to be put into perspective because many of these drugs did not show the expected effects.
Biological Rationale for New Drugs in the Bleeding Disorders Pipeline
Authors: Fogarty Patrick F. 
Published: December 2011

AbstractSince the introduction of replacement coagulation factor infusions for the treatment of hemophilia in the 1970s and subsequent improvements in the safety profile of available factor VIII (FVIII) and factor IX (FIX) concentrates, mortality among patients with hemophilia has improved considerably and now parallels that of the noncoagulopathic population in developed countries. Substantial morbidity, however, continues from the development of inhibitory antibodies, a recognized complication of clotting factor replacement; from infections and thrombosis complicating placement of central venous catheters, which are required in children with hemophilia due to frequent prophylactic infusions of coagulation factors with defined half-lives; and from disabling joint disease in individuals without access to costly prophylaxis regimens. In response to the need for long-acting, more potent, less immunogenic, and more easily administered therapies, an impressive array of novel agents is nearly ready for use in the clinical setting. These therapeutics derive from rational bioengineering of recombinant coagulation factors or from the discovery of nonpeptide molecules that have the potential to support hemostasis through alternative pathways. The number of novel agents in clinical trials is increasing, and many of the initial results are promising. In addition to advancing treatment of bleeding episodes or enabling adherence to prophylactic infusions of clotting factor concentrate, newer therapeutics may also lead to improvements in joint health, quality of life, and tolerability of iatrogenic or comorbidity-associated bleeding challenges.
Current Controversies in the Formation and Treatment of Alloantibodies to Factor VIII in Congenital Hemophilia A
Authors: Kruse-Jarres Rebecca 
Published: December 2011

Abstract
Hemophilia A is a rare bleeding disorder treated with numerous factor VIII (FVIII)–containing replacement concentrates. This treatment approach has led to the formation of alloantibodies that neutralize the FVIII activity (inhibitors) conveyed by these commercially available concentrates in ∼ 25% of patients with severe hemophilia A (FVIII activity < 1% of normal). This phenomenon significantly complicates the treatment of these patients and compromises the effectiveness and efficiency of these products to reverse or prevent bleeding complications. Studying the population with alloantibody inhibitors is imperative but difficult due to the overall small number of individuals affected and the heterogeneity within this limited group. Furthermore, few randomized clinical trials have been conducted to answer pertinent questions so many controversies persist. This article focuses on the conflicting data on the variables associated with alloantibody FVIII inhibitor development with a particular emphasis on age and intensity of first treatment, the role of primary prophylaxis regimens in modulating this phenomenon, and the degree of purity of FVIII product as a potential contributing risk factor. The optimal dosing regimen and type of FVIII replacement product that should be used to achieve the highest success rate in immune tolerance induction (ITI) protocols are also discussed, as well as whether the addition of immunomodulatory agents, especially rituximab, to ITI regimens enhances the durability of ITI and the eradication of alloantibody FVIII inhibitors.
Impact of Iron Assessment by MRI
Authors: Wood John C. 
Published: December 2011

Abstract
The use of magnetic resonance imaging (MRI) to estimate tissue iron was conceived in the 1980s, but has only become a practical reality in the last decade. The technique is most often used to estimate hepatic and cardiac iron in patients with transfusional siderosis and has largely replaced liver biopsy for liver iron quantification. However, the ability of MRI to quantify extrahepatic iron has had a greater impact on patient care and on our understanding of iron overload pathophysiology. Iron cardiomyopathy used to be the leading cause of death in thalassemia major, but is now relatively rare in centers with regular MRI screening of cardiac iron, through earlier recognition of cardiac iron loading. Longitudinal MRI studies have demonstrated differential kinetics of uptake and clearance among the difference organs of the body. Although elevated serum ferritin and liver iron concentration (LIC) increase the risk of cardiac and endocrine toxicities, some patients unequivocally develop extrahepatic iron deposition and toxicity despite having low total body iron stores. These observations, coupled with the advent of increasing options for iron chelation therapy, are allowing clinicians to more appropriately tailor chelation therapy to individual patient needs, producing greater efficacy with fewer toxicities. Future frontiers in MRI monitoring include improved prevention of endocrine toxicities, particularly hypogonadotropic hypogonadism and diabetes.
Real-World Use of Iron Chelators
Authors: Kwiatkowski Janet L. 
Published: December 2011

AbstractWhereas RBC transfusion therapy is lifesaving in thalassemia, obligatory iron loading accompanies such treatment and chelation therapy to remove and detoxify iron resulting from these chronic transfusions must therefore be administered. Morbidity and mortality in thalassemia is linked closely to the adequacy of chelation. Three chelators are currently available worldwide—deferoxamine, deferasirox, and deferiprone, although the latter is available in North America only in research protocols and compassionate use programs. These chelators can be used as monotherapy or in combination, although only the combination of deferiprone and deferoxamine has been extensively studied to date. Several factors, including chelator availability and its properties, drug tolerability, degree of organ-specific iron loading, ongoing transfusional iron burden, and patient preference, must be considered in the design of optimal, individualized chelation regimens, and these factors must periodically be reviewed and chelation adjusted accordingly. Ultimately, comparative effectiveness trials may help to determine the ideal strategy (eg, intensification of monotherapy or combined therapy including agents and doses) for treating various scenarios of organ-specific iron loading.
Immunomodulatory Mediators in Platelet Transfusion Reactions
Authors: Morrell Craig N. 
Published: December 2011

Abstract
Our appreciation of the roles that platelets play in vascular biology is constantly expanding. One of the major roles of platelets is in initiating and accelerating immune responses. Platelet transfusion may be associated with adverse inflammatory outcomes manifested as fever, discomfort, tachycardia, and respiratory issues. This may in part be due to immune mediators either expressed by activated platelets or released into the platelet media during platelet storage. This review will highlight some more recent knowledge gained regarding the platelet storage lesion and potential mediators of platelet transfusion reactions.
Fanconi Anemia
Authors: Soulier Jean 
Published: December 2011

Abstract
Fanconi anemia (FA) is the most frequent inherited cause of BM failure (BMF). Fifteen FANC genes have been identified to date, the most prevalent being FANCA, FANCC, FANCG, and FANCD2. In addition to classical presentations with progressive BMF during childhood and a positive chromosome breakage test in the blood, atypical clinical and/or biological situations can be seen in which a FA diagnosis has to be confirmed or eliminated. For this, a range of biological tools have been developed, including analysis of skin fibroblasts. FA patients experience a strong selective pressure in the BM that predisposes to clonal evolution and to the emergence in their teens or young adulthood of myelodysplasia syndrome (MDS) and/or acute myeloid leukemia (AML) with a specific pattern of somatic chromosomal lesions. The cellular mechanisms underlying (1) the hematopoietic defect which leads to progressive BMF and (2) somatic clonal evolutions in this background, are still largely elusive. Elucidation of these mechanisms at the molecular and cellular levels should be useful to understand the physiopathology of the disease and to adapt the follow-up and treatment of FA patients. This may also ultimately benefit older, non-FA patients with aplastic anemia, MDS/AML for whom FA represents a model genetic condition.
Relapsed/Refractory Diffuse Large B-Cell Lymphoma
Authors: Friedberg Jonathan W. 
Published: December 2011

Abstract
Despite overall improvements in outcomes of diffuse large B-cell lymphoma (DLBCL), approximately one-third of patients will develop relapsed/refractory disease that remains a major cause of morbidity and mortality. Novel insights from gene-expression analyses have increased our understanding of chemotherapy resistance and yielded rational targets for therapeutic intervention to both prevent and treat relapsed/refractory DLBCL. The clinical approach to relapsed/refractory DLBCL should include high-dose therapy and autologous stem cell transplantation (HD-ASCT) with curative intent in patients without comorbidities. Results from the recently reported CORAL study suggest that patients refractory to rituximab-containing regimens have inferior outcomes with HD-ASCT. Ongoing efforts to improve ASCT include novel conditioning regimens and evaluation of maintenance approaches after ASCT. Unfortunately, because the majority of patients are not eligible for ASCT due to refractory disease or age/comorbidities, these approaches have limited impact. The large group of patients not eligible for ASCT have incurable disease and should be referred for clinical trials of rationally targeted agents.
The Role of Platelets in Atherothrombosis
Authors: Kaplan Zane S. , Jackson Shaun P. 
Published: December 2011

Abstract
Platelets have evolved highly specialized adhesion mechanisms that enable cell-matrix and cell-cell interactions throughout the entire vasculature irrespective of the prevailing hemodynamic conditions. This unique property of platelets is critical for their ability to arrest bleeding and promote vessel repair. Platelet adhesion under conditions of high shear stress, as occurs in stenotic atherosclerotic arteries, is central to the development of arterial thrombosis; therefore, precise control of platelet adhesion must occur to maintain blood fluidity and to prevent thrombotic or hemorrhagic complications. Whereas the central role of platelets in hemostasis and thrombosis has long been recognized and well defined, there is now a major body of evidence supporting an important proinflammatory function for platelets that is linked to host defense and a variety of autoimmune and inflammatory diseases. In the context of the vasculature, experimental evidence indicates that the proinflammatory function of platelets can regulate various aspects of the atherosclerotic process, including its initiation and propagation. The mechanisms underlying the proatherogenic function of platelets are increasingly well defined and involve specific adhesive interactions between platelets and endothelial cells at atherosclerotic-prone sites, leading to the enhanced recruitment and activation of leukocytes. Through the release of chemokines, proinflammatory molecules, and other biological response modulators, the interaction among platelets, endothelial cells, and leukocytes establishes a localized inflammatory response that accelerates atherosclerosis. These inflammatory processes typically occur in regions of the vasculature experiencing low shear and perturbed blood flow, a permissive environment for leukocyte-platelet and leukocyte-endothelial interactions. Therefore, the concept has emerged that platelets are a central element of the atherothrombotic process and that future therapeutic strategies to combat this disease need to take into consideration both the prothrombotic and proinflammatory function of platelets.
The Hepcidin-Ferroportin System as a Therapeutic Target in Anemias and Iron Overload Disorders
Authors: Ganz Tomas , Nemeth Elizabeta 
Published: December 2011

Abstract
The review summarizes the current understanding of the role of hepcidin and ferroportin in normal iron homeostasis and its disorders. The various approaches to therapeutic targeting of hepcidin and ferroportin in iron-overload disorders (mainly hereditary hemochromatosis and β-thalassemia) and iron-restrictive anemias (anemias associated with infections, inflammatory disorders, and certain malignancies, anemia of chronic kidney diseases, and iron-refractory iron-deficiency anemia) are also discussed.
New Ways to Use DNA Methyltransferase Inhibitors for the Treatment of Myelodysplastic Syndrome
Authors: Gore Steven D. 
Published: December 2011

AbstractOngoing analysis of the seminal AZA-001 study has taught many important lessons in the use of DNA methyltransferase (DNMT) inhibitors. The data emphasize the importance of patience in the use of these drugs, with several cycles required for the manifestations of hematologic responses. Improved survival in patients with high-risk myelodysplastic syndrome (MDS) treated with azacitidine extends to patients with any International Working Group–defined hematologic response; however, the benefit to patients with stable disease is less clear. A great deal remains to be learned about the optimal dosing and scheduling of the DNMT inhibitors, alone and in combination. New information on the impact of DNMT inhibitors on the immune system and on stem cells will likely lead to novel uses of these drugs in MDS and other hematologic and nonhematologic malignancies.