bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alternative Strategies for Gene Therapy of Hemophilia
Authors: Montgomery Robert R. , Shi Qizhen 
Published: January 2011

Abstract
Hemophilia A and B are monogenic disorders that were felt to be ideal targets for initiation of gene therapy. Although the first hemophilia gene therapy trial has been over 10 years ago, few trials are currently actively recruiting. Although preclinical studies in animals were promising, levels achieved in humans did not achieve long-term expression at adequate levels to achieve cures. Transplantation as a source of cellular replacement therapy for both hemophilia A and B have been successful following liver transplantation in which the recipient produces normal levels of either factor VIII (FVIII) or factor IX (FIX). Most of these transplants have been conducted for the treatment of liver failure rather than for “curing” hemophilia. There are a variety of new strategies for delivering the missing clotting factor through ectopic expression of the deficient protein. One approach uses hematopoietic stem cells using either a nonspecific promoter or using a lineage-specific promoter. An alternative strategy includes enhanced expression in endothelial cells or blood-outgrowth endothelial cells. An additional approach includes the expression of FVIII or FIX intraarticularly to mitigate the intraarticular bleeding that causes much of the disability for hemophilia patients. Because activated factor VII (FVIIa) can be used to treat patients with inhibitory antibodies to replacement clotting factors, preclinical gene therapy has been performed using platelet- or liver-targeted FVIIa expression. All of these newer approaches are just beginning to be explored in large animal models. Whereas improved recombinant replacement products continue to be the hallmark of hemophilia therapy, the frequency of replacement therapy is beginning to be addressed through longer-acting replacement products. A safe cure of hemophilia is still the desired goal, but many barriers must still be overcome.
Hemophilia: New Protein Therapeutics
Authors: Pipe Steven W. 
Published: January 2011

AbstractTherapeutic advances for patients with hemophilia have resulted in reduced mortality, improved joint outcomes, safety from blood-transmitted pathogens, improved quality of life, and a normalized life span in the developed world. The production of recombinant coagulation factors has increased the worldwide capacity for replacement therapy and facilitated aggressive prophylactic therapy. However, this has come at significant cost, and barriers remain to broad application of prophylaxis. Recombinant DNA technology remains a promising platform to develop novel hemophilia therapeutics with improved functional properties to try to overcome some of these remaining barriers. Bioengineering strategies have produced novel therapeutics with increased production efficiency, increased potency and resistance to inactivation, prolonged plasma half-lives, and reduced immunogenicity. Alternative nonbiologic therapies may lead to new treatment paradigms. The current pipeline of new technologies and products is promising and growing with several agents already advancing from preclinical to clinical trials.
Adolescents and Young Adults with Acute Lymphoblastic Leukemia
Authors: Stock Wendy 
Published: January 2011

Abstract
During the last decade, increasing attention has been paid to a unique group of patients with acute lymphoblastic leukemia (ALL) who lie at the crossroad of therapeutic care by pediatric and adult hematologists/oncologists. ALL is a disease that affects infants, children, adolescents, and adult patients. With current therapies, the vast majority of children with ALL are now long-term survivors; unfortunately, the same good results have not yet been obtained for adults with ALL. This review will describe current controversies surrounding the treatment of adolescents and young adults with ALL—a group who finds themselves in the transition from “pediatric” to “adult” treatment approaches. The review focuses on recent insights into disease biology, prognostic factors, and treatment outcomes that have led to a series of prospective clinical trials specifically designed for adolescents and younger adults (AYAs) with ALL. These trials have been designed to provide important new clinical, psychosocial, and biological insights, and to further improve the survival of this challenging and unique group of patients.
Duration of Anticoagulation: Applying the Guidelines and Beyond
Authors: Bauer Kenneth A. 
Published: January 2011

Abstract
Despite an improved understanding of the risk factors underlying venous thromboembolism (VTE), extensive clinical investigation, and detailed clinical guidelines, the decision to extend anticoagulation indefinitely for an individual patient with VTE is often problematic. Patients with VTE in association with major surgery, trauma, immobilization, or pregnancy are at relatively low risk of recurrence and generally do not require more than 3 to 6 months of anticoagulant therapy. For patients with a first unprovoked, or idiopathic, episode of VTE, an individualized approach should be taken in deciding on the duration of anticoagulation based on the patient's recurrence and bleeding risk, as well as their personal preference. Although the presence of genetic thrombophilic disorders (factor V Leiden and prothrombin G20210A gene mutations; deficiencies of antithrombin, protein C, and protein S) predispose patients to a first episode of VTE, there is inconsistent data on whether testing for these defects changes patient outcomes or should alter their management. In patients with a single unprovoked VTE, measurement of D-dimer several weeks following the completion of anticoagulant therapy appears useful in stratifying patients with a first unprovoked episode of VTE with regard to recurrence risk. Through a series of clinical vignettes, the utility of the laboratory in risk-stratifying patients with respect to recurrence risk will be discussed, along with decision making regarding the duration of anticoagulation. The potential impact of having a nonremovable inferior vena caval filter will also be addressed.
The Post-Thrombotic Syndrome
Authors: Kahn Susan R. 
Published: January 2011

AbstractThe post-thrombotic syndrome (PTS) is an important chronic complication of deep vein thrombosis (DVT). The present review focuses on risk determinants of PTS after DVT and available means to prevent and treat PTS. More than one-third of patients with DVT will develop PTS, and 5% to 10% of patients develop severe PTS, which can manifest as venous ulcers. PTS has an adverse impact on quality of life as well as significant socioeconomic consequences. The main risk factors for PTS are persistent leg symptoms 1 month after acute DVT, anatomically extensive DVT, recurrent ipsilateral DVT, obesity, and older age. Subtherapeutic dosing of initial oral anticoagulation therapy for DVT treatment may also be linked to subsequent PTS. By preventing the initial DVT and DVT recurrence, primary and secondary prophylaxis of DVT will prevent cases of PTS. Daily use of elastic compression stockings for 2 years after proximal DVT appears to reduce the risk of PTS; however, uncertainty remains regarding optimal duration of use, optimal compression strength, and usefulness after distal DVT. The cornerstone of managing PTS is compression therapy, primarily using elastic compression stockings. Venoactive medications such as aescin and rutosides may provide short-term relief of PTS symptoms. Further studies to elucidate the pathophysiology of PTS, to identify clinical and biological risk factors, and to test new preventive and therapeutic approaches to PTS are needed.
Warfarin Versus New Agents: Interpreting the Data
Authors: Ansell Jack 
Published: January 2011

AbstractStroke prevention in atrial fibrillation (AF) is a rapidly expanding indication for lifelong oral anticoagulation. The vitamin K antagonists (VKAs) effectively prevent stroke, but are notoriously difficult to manage and are associated with frequent adverse events. These factors account for the widespread underuse of warfarin for patients with AF who are qualified candidates for therapy. New oral anticoagulants with different mechanisms of action are beginning to exit phase III trials and may replace the VKAs for a number of indications, especially AF. The oral direct thrombin and Xa inhibitors are furthest along in development. Dabigatran etexilate, a thrombin inhibitor, has recently shown excellent outcomes in the prevention of stroke in patients with AF. The oral Xa inhibitors are still in phase III trials for stroke prevention in AF, but results from trials for other indications look promising. These short-acting, short-duration, unmonitored drugs are not without limitations and potential adverse effects. The perceived drawbacks of the VKAs may actually be assets in the management of patients with AF, and the pros and cons of each class of drug must be taken into account as physicians consider or patients request transition to a new class of oral anticoagulants.
Long-Term Physiological Side Effects After Allogeneic Bone Marrow Transplantation
Authors: Mohty Mohamad , Apperley Jane F. 
Published: January 2011

Abstract
Allogeneic bone marrow transplantation (allo-BMT) or stem cell transplantation has the potential to cure a significant proportion of patients with otherwise fatal diseases. At present, immediate survival is no longer the sole concern after allo-BMT, because many patients can survive the acute complications of the procedure and remain free of their original disease for several years. Although long-term allo-BMT survivors generally enjoy good health, for many others cure or control of the underlying disease is not accompanied by full restoration of health. The long-term physiologic effects after allo-BMT include nonmalignant organ or tissue dysfunction; changes in quality of life; infections related to delayed, or abnormal, immune reconstitution; and secondary cancers. These long-term complications and the features of chronic graft-versus-host disease (GVHD) symptoms are heterogeneous in nature, time of onset, duration, and severity. The underlying origin of these complications is often multifactorial, with chronic GVHD being the most challenging risk factor. The main aims of this review are to present transplant physicians and health care providers with an overview of these malignant and nonmalignant late complications, with a special focus on chronic GVHD. A close partnership between the transplant center, organ-specific specialties, and local primary care providers is a key component of preventive medicine. The patient can play a major role through engagement in health maintenance behaviors.
Comorbidities and Hematopoietic Cell Transplantation Outcomes
Authors: Sorror Mohamed L. 
Published: January 2011

AbstractConventional allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment option for various hematological diseases due, in part to high-dose conditioning and, in part, to graft-versus-tumor effects. Reduced-intensity or non-myeloablative conditioning regimens have relied mostly on graft-versus-tumor effects for disease control, and their advent has allowed relatively older and medically infirm patients to be offered allo-HCT. However, both HCT modalities have been associated with organ toxicities and graft-versus-host disease, resulting in substantial non-relapse mortality. It has become increasingly important to optimize pre-transplant risk assessment in order to improve HCT decision making and clinical trial assignments. Single-organ comorbidity involving liver, lung, heart, or kidney before HCT has been traditionally found to cause organ toxicity after HCT. Recent efforts have resulted in the advent of a weighted scoring system that could sensitively capture multiple-organ comorbidities prior to HCT. The HCT-comorbidity index (HCT-CI) has provided better prediction of HCT-related morbidity and mortality than other non-HCT-specific indices. Subsequent studies, with the exception of a few studies with modest numbers of patients, have confirmed the prognostic importance of the HCT-CI. Further, the HCT-CI has been consolidated with various disease-specific and patient-specific risk factors to refine assignments of patients to the appropriate HCT setting. Ongoing studies are addressing prospective validation of the HCT-CI, furthering our understanding of biological aging, and enhancing the applicability of the HCT-CI comorbidity coding. Future knowledge of the impacts of multiple comorbidities on post-HCT toxicities might guide new prophylactic and therapeutic interventions to lessen the procedure's mortality.
Health-Related Quality of Life Following Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Bevans Margaret 
Published: January 2011

Abstract
It is common knowledge that an allogeneic hematopoietic stem cell transplantation (HSCT) will have an enormous impact on the lives of transplant recipients and their families. Once an appropriate donor is identified, the curative potential of this treatment often drives the decision to proceed knowing that there will be intense physiologic toxicities and adverse effects on health-related quality of life (HRQL). Twenty-five years ago, HRQL was identified as an efficacy parameter in the evaluation of new anticancer drug therapy. Overall, the evidence suggests that an allogeneic HSCT has a significant impact on the overall HRQL of recipients, which is a result of decrements across all dimensions, including a significant symptom profile. The degree of impact on overall HRQL and the multiple dimensions varies across the transplant trajectory. Specific HRQL dimensions, such as physical function and symptoms, are easily incorporated into a clinician's assessment whereas other dimensions (eg, psychosocial) are less commonly integrated. The translation of HRQL results to improve clinical practice is not well established. Clinicians are often uncertain when to assess the scope of HRQL and how to interpret the information in a clinically meaningful way. The purpose of this review is to highlight the quality-of-life effects of allogeneic HSCT and discuss application into clinical practice.
Host Factors for Risk and Survival in Lymphoma
Authors: Dave Sandeep S. 
Published: January 2011

Abstract
All cancers arise from complex interactions between aspects of the patient (host) biology and the environment. Once tumors arise, they frequently remain dependent on interactions with their microenvironment for their growth and proliferation. In this review, we examine the contributions of the host genetics and environmental exposures to the development of lymphoma. We will further examine the interactions of the tumor and the microenvironment that influence tumor growth and proliferation.
Novel Agents for Follicular Lymphoma
Authors: Leonard John P. , Martin Peter 
Published: January 2011

Abstract
Unlabeled and radiolabeled anti-CD20 monoclonal antibodies have had a significant impact in the care of patients with follicular lymphoma (FL) over the past decade. More recently, bendamustine has demonstrated activity in refractory FL, and has been explored as initial therapy and in novel combinations. Whereas outcomes for this patient population have significantly improved, there remains substantial unmet need for patients who require more effective and better-tolerated therapies. Novel anti-CD20 antibodies and other immunotherapies against different B-cell antigens are under active investigation. The proteosome inhibitor bortezomib and the immunomodulatory agent lenalidomide have demonstrated single-agent activity and are currently in randomized trials. Other novel compounds have demonstrated activity in broad-based clinical studies in B-cell malignancies. However, considerable challenges remain in efficiently demonstrating which patient subsets can benefit from these novel compounds and which combinations may have the greatest clinical benefit in further improving outcomes for patients with FL.
Signal Transduction Inhibitor Therapy for Lymphoma
Authors: Witzig Thomas E. , Gupta Mamta 
Published: January 2011

AbstractCurrent research in lymphoma is focused on two areas of lymphoma biology—the signal transduction pathways used to maintain the growth of malignant lymphocytes and the role of the tumor microenvironment in lymphoma growth and survival. This review focuses on three signaling pathways: the phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway, the B-cell receptor/spleen tyrosine kinase (BCR/Syk) pathway, and the protein kinase C-beta (PKC-β) pathway, known to be important to lymphoma cells. The mTOR inhibitors temsirolimus and everolimus have demonstrated antitumor activity in all types of lymphoma, the Syk inhibitor fostamatinib has activity in diffuse large B-cell lymphoma and chronic lymphocytic leukemia, and the PKC-β inhibitor enzastaurin is being used as consolidation therapy after remission in diffuse large B-cell lymphoma. This review discusses the biology behind the development of each new agent and the results of initial clinical trials. The goal is to provide the hematologist/oncologist background information on these new agents and understand their current and potential role in the management of patients.
Anemia in Elderly Patients: An Emerging Problem for the 21st Century
Authors: Vanasse Gary J. , Berliner Nancy 
Published: January 2011

Abstract
Anemia is a significant problem in elderly patients. Although many anemic elderly patients can be diagnosed with nutritional deficiency, anemia of chronic inflammation or comorbid diseases that explain their decreased hematocrit, the etiology of anemia in a significant fraction remains obscure. There is evidence to suggest that the hematopoietic stem cell displays increasing erythropoietin (EPO) resistance with age. EPO levels rise in elderly, nonanemic patients, and it is hypothesized that there is an interplay between this rising demand for EPO and the decreasing ability of the aging kidney to produce adequate hormone to meet that need. There is further considerable evidence that aging is associated with increased proinflammatory cytokine expression and that many of these cytokines can contribute to EPO insensitivity. Consequently, genetic variation in the expression of these proinflammatory cytokines may influence the development of anemia in elderly patients, both through induction of hepcidin expression (anemia of inflammation) and through cytokine suppression of erythroid colony formation. The impact of inflammatory mediators, EPO insensitivity, and other factors that may act on the hematopoietic stem cell to decrease erythropoiesis are under active study and should serve to elucidate the pathophysiology of this important cause of morbidity and mortality in elderly individuals. A better understanding of the pathophysiology of anemia in elderly patients should provide critical entry points for interventions that will improve survival and quality of life in the aging population.
Anemia of Inflammation
Authors: Roy Cindy N. 
Published: January 2011

Abstract
Inflammation arising from various etiologies, including infection, autoimmune disorders, chronic diseases, and aging, can promote anemia. The anemia of inflammation (AI) is most often normocytic and normochromic and is usually mild. Characteristic changes in systemic iron handling, erythrocyte production, and erythrocyte life span all contribute to AI. The preferred treatment is directed at the underlying disease. However, when the inflammatory insult is intractable, or the cause has not been diagnosed, there are limited options for treatment of AI. Because anemia is a comorbid condition that is associated with poor outcomes in various chronic disease states, understanding its pathogenesis and developing new tools for its treatment should remain a priority. Hepcidin antimicrobial peptide has taken center stage in recent years as a potent modulator of iron availability. As the technology for quantitative hepcidin analysis improves, hepcidin's role in various disease states is also being revealed. Recent insights concerning the regulatory pathways that modify hepcidin expression have identified novel targets for drug development. As the field advances with such therapeutics, the analysis of the impact of normalized hemoglobin on disease outcomes will confirm whether anemia is a reversible independent contributor to the morbidity and mortality associated with inflammatory diseases.
Hematologic Disorders after Solid Organ Transplantation
Authors: Smith Eileen P. 
Published: January 2011

Abstract
The evaluation of hematologic disorders after solid organ transplantation (SOT) must take into account issues unique to the post-transplant setting that influence the development of anemia and single or multi-lineage cytopenias. Attention to the time of onset of cytopenia(s) is important, because the disorders of passenger lymphocyte syndrome, transplant-related thrombotic microangiopathy, hemophagocytic syndrome, and graft-versus-host disease typically occur during the first few months after SOT, and post-transplant lymphoproliferative disorder usually occurs within the first year. Drug-related anemia and cytopenia(s) occur due to a variety of mechanisms, including drug-induced hemolysis and marrow suppression and perturbation of T-cell subsets by the immunosuppressive agents, leading to immune dysregulation and autoimmunity. Viral infections can cause direct suppression of hematopoiesis, and a variety of opportunistic infections can precipitate acquired hemophagocytic syndrome, a frequently lethal systemic inflammatory disorder. Early investigation of pancytopenia by bone marrow biopsy is warranted, because it is often the presenting symptom of one or multiple life-threatening pathologies after SOT, such as graft-versus host disease, post-transplant lymphoproliferative disorder, hemophagocytic syndrome, or severe opportunistic infections, and these entities may have a better prognosis if early interventions are undertaken.
Systemic Light-Chain Amyloidosis: Advances in Diagnosis, Prognosis, and Therapy
Authors: Cohen Adam D. , Comenzo Raymond L. 
Published: January 2011

Abstract
Systemic light-chain amyloidosis (AL) is caused by misfolded immunoglobulin light-chain proteins that aggregate and deposit as unique fibrils, ultimately leading to organ failure and death. Recent developments that have significantly aided the management of patients with AL include diagnostic techniques for definitive typing of amyloid deposits by use of laser microdissection with mass spectrometry and customized protein bioinformatics, and validated staging and response-scoring systems that improve clinical trial design. The widespread use of cardiac biomarker staging and serum-free light-chain levels to evaluate response to therapy has also improved care. Standard therapies such as oral melphalan and dexamethasone or autologous stem cell transplant continue to be important options, while thalidomide and its analogs, lenalidomide and pomalidomide, and the proteasome-inhibitor bortezomib have activity in AL and have expanded our armamentarium. Continued improvement in outcomes, however, will require the commitment and cooperation of pharmaceutical companies, regulatory agencies, academic investigators, and cooperative groups/consortia. This effort will involve the conduct of well-designed clinical trials of new agents and combinations within a modern framework that categorizes the study populations of patients with AL, defines the end points appropriate to those populations and to the different phases of clinical trials, employs the newly available staging and response criteria, and standardizes adverse event reporting.