bluuebunny/crossref_metadata_2025 huggingface dataset:
The Brain-Bone-Blood Triad: Traffic Lights for Stem-Cell Homing and Mobilization
Authors: Lapidot Tsvee , Kollet Orit
Published: January 2011

Navigation of transplanted stem cells to their target organs is essential for clinical bone marrow reconstitution. Recent studies have established that hematopoietic stem cells (HSCs) dynamically change their features and location, shifting from quiescent and stationary cells anchored in the bone marrow to cycling and motile cells entering the circulation. These changes are driven by stress signals. Bidirectional migrations to and from the bone marrow are active processes that form the basis for HSC transplantation protocols. However, how and why HSCs enter and exit the bone marrow as part of host defense and repair is not fully understood. The development of functional, preclinical, immune-deficient NOD/SCID (non-obese diabetic-severe combined immunodeficiency) mice transplantation models has enabled the characterization of normal and leukemic human HSCs and investigation of their biology. Intensive research has revealed multiple tasks for the chemokine SDF-1 (stromal cell-derived factor-1, also known as CXCL12) in HSC interactions with the microenvironment, as well as the existence of overlapping mechanisms controlling stress-induced mobilization and enhanced HSC homing, sequential events of major physiological relevance. These processes entail dynamically interacting, multi-system aspects that link the bone marrow vasculature and stromal cells with the nervous and immune systems. Neural cues act as an external pacemaker to synchronize HSC migration and development to balance bone remodeling via circadian rhythms in order to address blood and immune cell production for the physiological needs of the body. Stress situations and clinical HSC mobilization accelerate leukocyte proliferation and bone turnover. This review presents the concept that HSC regulation by the brain-bone-blood triad via stress signals controls the bone marrow reservoir of immature and maturing leukocytes.
The Past: What We Have Learned in the Last Decade
Authors: Borchmann Peter , Engert Andreas
Published: January 2011

Hodgkin lymphoma (HL) has become a curable malignancy for most patients during the last decades. However, many controversies still exist on the optimal strategy of how to cure our patients. The key question is how to balance the risks and toxicities of chemotherapy and radiotherapy against the need for a definite treatment for early or advanced-stage HL patients. However, although many studies have been conducted and reported during the past decade, interpretation of their results and treatment recommendations might vary significantly in different countries. For example, early-stage HL might be divided into two different subgroups: early favorable and early unfavorable or not. Treatment of early-stage HL might include radiotherapy (“combined modality”) or not. Depending on the extent of radiotherapy, the schedule and number of chemotherapy cycles are also questioned. For advanced-stage HL, the situation is not much different. Compared with ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine), the more aggressive escalated BEACOPP regimen (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, and prednisone) is highly effective, but also raises concern due to excessive toxicity. Thus, there is a controversy about the standard of care for advanced HL patients. Because no mature results comparing these approaches with each other are currently available, it remains our duty to share the preliminary information with our patients and to figure out the most appropriate individual treatment strategy. Of course, the discussion of these issues is influenced by experiences and preferences. In contrast, in this article, we will try to focus on the available scientific evidence regarding the first-line treatment of HL. Of course, focusing on the last decade necessarily exclude the most recent results from ongoing studies. Thus, even though this article comprises treatment recommendations for HL patients, the best treatment certainly still is within properly designed prospective clinical trials.
The Present: Optimizing Therapy—Too Much or Too Little?
Authors: Bartlett Nancy L.
Published: January 2011

Despite the use of less toxic chemotherapy and more limited doses and fields of radiation, the prognosis for patients with all stages of classical Hodgkin lymphoma (HL) has continued to improve over the last 20 years. The challenge today is better identification of prognostic markers that will allow even further reduction of therapy in the most favorable subsets and new approaches for those who have a high risk of failure with current approaches. Most ongoing clinical trials for newly diagnosed HL base therapy decisions on the result of an interim restaging PET/CT, de-escalating for early responders and escalating for patients with a suboptimal response. While awaiting the results of these important trials, the debates rage on regarding the use of consolidative radiotherapy in early stage HL and the use of escalated BEACOPP in advanced stage disease. Unfortunately, we still face the very difficult decision with nearly every patient with HL of “too much,” risking long-term consequences, or “too little,” risking relapse and the need for additional toxic therapy. At present, we need to make these very difficult initial treatment decisions with inadequate data, but reassured by the excellent outcomes for most patients and encouraged by the new agents available for those who fail first-line therapy.
Assessing New Therapies and Their Overall Impact in Myelofibrosis
Authors: Mesa Ruben A.
Published: January 2011

Clinical management of myelofibrosis (MF)—whether primary or arising from an antecedent myeloproliferative neoplasm (post-essential thrombocythemia/polycythemia vera MF)—is currently in a period of transition that began with the discovery of the JAK2-V617F mutation 5 years ago. Selective JAK2 inhibitors have been developed, and clinical trials thus far have demonstrated that several of these agents meaningfully reduce MF-associated splenomegaly and constitutional symptoms. JAK2 inhibitors have durable benefits, act across the spectrum of MF subtypes, and provide a level of symptomatic benefit not seen with previous generations of nontargeted therapies. However, the JAK2 inhibitors can cause anemia and/or gastrointestinal disturbance, and their impact on JAK2 allele burden and the natural history is not yet fully defined. Several additional therapies that do not directly target JAK2 (eg, immunomodulatory drugs, histone deacetylase inhibitors, and inhibitors of the mammalian target of rapamycin [mTOR]) may ameliorate MF-associated anemia and morbidity-inducing symptoms. Balancing the potential benefits of these new agents against the risks and benefits of allogeneic stem cell transplantation (which can be curative, but carries a high risk of treatment-associated morbidity and mortality) requires an accurate estimation of the prognosis for an individual patient. Enhanced prognostic modeling systems are helping us to better characterize prognosis in MF patients not only at diagnosis, but also along the dynamic and variable course of the illness. Future advancements in the efficacy of MF-targeted therapy will likely arise from new pathogenetic insights and from combining JAK2 inhibitors with other agents.
Chronic Myeloid Leukemia 2010: Where Are We Now and Where Can We Go?
Authors: Radich Jerald P.
Published: January 2011

Chronic myeloid leukemia is a model of how the molecular understanding of a disease can provide the platform for therapy and diagnostics. Clinicians are now empowered with first- and second-generation tyrosine kinases, as well as molecular tools to monitor disease and characterize resistance. However, there are still unanswered questions regarding optimization of therapy, the utility of molecular monitoring, and the search (or need) of “cure” that bears thought. In this review, we will discuss these issues, as they provide a roadmap for what may lie ahead in the therapy of other hematologic malignancies, particular the other myeloproliferative syndromes, where specific genetic lesions, and targeted therapy, are now being realized.
Rethinking Disease Definitions and Therapeutic Strategies in Essential Thrombocythemia and Polycythemia Vera
Authors: Harrison Claire
Published: January 2011

The seminal discovery of the JAK2V617F mutation, which is highly prevalent in Philadelphia-negative myeloproliferative disorders, now renamed neoplasms, triggered an almost unprecedented explosion of interest and data in the field. Descriptions of additional mutations in exon 12 of JAK2, at position 515 in MPL, and a number of other mutations at low frequency followed these discoveries. These advances in our understanding of molecular pathogenesis of these conditions coincided with the publication of results from two major clinical studies, ECLAP and PT-1, which contributed important clinical insights and facilitated significant correlative data collection. This article, focusing mainly upon essential thrombocythemia and polycythemia vera, reviews four major themes: the impact upon classification of these disorders considering a radical review of current terminology, and then three areas pertinent to clinical management: the indications for cytoreductive therapy in which the key targets are to reduce thrombohemorrhagic complications, relieve disease-related symptoms, and minimize the risk of transformation to secondary myeloid malignancy such as myelodysplasia, leukemia, and secondary myelofibrosis; and second reviewing current and, last, future therapeutic options, in particular interferon and JAK2 inhibitors.
Treating the “Older” Adult With Acute Lymphoblastic Leukemia
Authors: Marks David I.
Published: January 2011

Acute lymphoblastic leukemia (ALL) in adults is a rare disease. The results of therapy remain unsatisfactory, and progress has been relatively slow. This article will focus on curative therapy in patients aged 30 to 60 years, but will also discuss the management of elderly patients with ALL. Recent large trials have increased our knowledge of the factors that determine outcome, and have clarified the role of blood and marrow transplantation in the management of this disease. These trials have also highlighted the major issues we need to focus on if we are to improve outcomes. This article describes the results of chemotherapy and blood and marrow transplantation for Philadelphia chromosome negative and positive adult ALL in the “older” adult patient, but also critically examines the major controversies and suggests how they might be resolved. The role of allografting in adult ALL is comprehensively discussed. Results of recent studies on T-cell ALL and reduced-intensity allografting are reviewed. A better understanding of the biology of the disease (including gene profiling) may allow individualization of therapy and, in time, targeted therapy.
Thrombocytopenia in the Intensive Care Unit Patient
Authors: Greinacher Andreas , Selleng Kathleen
Published: January 2011

The many comorbidities in the severely ill patient also make thrombocytopenia very common (∼ 40%) in intensive care unit patients. The risk of bleeding is high with severe thrombocytopenia and is enhanced in intensive care patients with mild or moderately low platelet counts when additional factors are present that interfere with normal hemostatic mechanisms (eg, platelet function defects, hyperfibrinolysis, invasive procedures, or catheters). Even if not associated with bleeding, low platelet counts often influence patient management and may prompt physicians to withhold or delay necessary invasive interventions, reduce the intensity of anticoagulation, order prophylactic platelet transfusion, or change anticoagulants due to fear of heparin-induced thrombocytopenia. One approach to identify potential causes of thrombocytopenia that require specific interventions is to consider the dynamics of platelet count changes. The relative decrease in platelet counts within the first 3 to 4 days after major surgery is informative about the magnitude of the trauma or blood loss, whereas the dynamic of the platelet count course thereafter shows whether or not the physiologic compensatory mechanisms are working. A slow and gradual fall in platelet counts developing over 5 to 7 days is more likely to be caused by consumptive coagulopathy or bone marrow failure, whereas any abrupt decrease (within 1–2 days) in platelet counts manifesting after an initial increase in platelet counts approximately 1 to 2 weeks after surgery strongly suggests immunologic causes, including heparin-induced thrombocytopenia, other drug-induced immune thrombocytopenia, and posttransfusion purpura.
Thrombosis in Cancer: An Update on Prevention, Treatment, and Survival Benefits of Anticoagulants
Authors: Lee Agnes Y.Y.
Published: January 2011

Thromboembolism is a common, complex, and costly complication in patients with cancer. Management has changed significantly in the past decade, but remains firmly dependent on the use of anticoagulants. Low-molecular-weight heparin is the preferred anticoagulant for prevention and treatment, although its limitations open opportunities for newer oral antithrombotic agents to further simplify therapy. Multiple clinical questions remain, and research is focusing on identifying high-risk patients who might benefit from primary thromboprophylaxis, treatment options for those with established or recurrent thrombosis, and the potential antineoplastic effects of anticoagulants. Risk-assessment models, targeted prophylaxis, anticoagulant dose escalation for treatment, and ongoing research studying the interaction of coagulation activation in malignancy may offer improved outcomes for oncology patients.
Recombinant Factor VIIa: An Assessment of Evidence Regarding Its Efficacy and Safety in the Off-Label Setting
Authors: Logan Aaron C. , Goodnough Lawrence T.
Published: January 2011

Recombinant human factor VIIa (rFVIIa) is approved by the US Food and Drug Administration for use in the setting of hemorrhage associated with factor VIII or factor IX inhibitors in patients with congenital or acquired hemophilia. This indication represents only a small number of bleeding conditions. Since it became available, rFVIIa has been increasingly used in the management of off-label indications, ranging from emergent hemostasis in traumatic hemorrhage to prophylactic hemostasis in patients undergoing major surgery. Prominent off-label indications include the management of patients with coagulopathies, such as occurs in trauma patients experiencing massive and uncontrolled hemorrhage, and in patients undergoing cardiovascular surgery with cardiopulmonary bypass. Other occasions for use occur in patients with intact coagulation systems, with nontraumatic intracranial hemorrhage being the most common in this group. Uncertainties regarding the efficacy and safety associated with use of rFVIIa in these off-label scenarios have led to evidence-based assessments of patient outcomes, including mortality, the rate of thromboembolic adverse events, and posttreatment functional status. We review the evidence regarding the efficacy and safety of this important, but controversial, hemostatic agent in the off-label setting.
Pregnancy and Commonly Used Drugs in Hematology Practice
Authors: Koren Gideon , Lishner Michael
Published: January 2011

When a woman suffering from a hematological condition is contemplating pregnancy, she may need to continue the use of medications that do not have sufficient evidence of fetal safety. We discuss the evidence existing for some therapies of major hematological conditions in the context of major principles in clinical teratology. It is critical to always balance the potential fetal risks of the drug in question against the maternal and fetal risks of the untreated hematological condition.
Consultative Hematology: The Pregnant Patient Pregnancy Loss
Authors: Bates Shannon M.
Published: January 2011

The presence of antiphospholipid antibodies has been associated with an increased risk of recurrent pregnancy loss, and there is evidence to suggest that antithrombotic therapy improves the likelihood of a successful outcome in affected women. Recent studies suggest an association between hereditary thrombophilia and pregnancy loss, although a causal role remains controversial. Although the available data are limited and flawed, there is increasing use of antithrombotic therapy in thrombophilic women with a history of pregnancy failure. Given the absence of proven effective therapy in women with unexplained recurrent loss, there is also growing pressure to intervene with antithrombotics in women with no known underlying thrombophilia. This article reviews the evidence for an association between thrombophilia and recurrent pregnancy loss and the data regarding the use of antithrombotic therapy for prevention of loss—an area that remains particularly challenging because of the paucity of good quality data upon which to base clinical decisions.
Evidence Base for the Management of Venous Thromboembolism in Pregnancy
Authors: Rodger Marc
Published: January 2011

Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is a leading cause of maternal mortality during pregnancy. DVT and PE are commonly suspected due to many mimicking signs and symptoms that are normal in pregnancy. However, validated diagnostic approaches are lacking, and a fear of teratogenic/oncogenic exposure from imaging procedures affects the acceptability of diagnostic approaches used for VTE during pregnancy. DVT and PE treatment in pregnancy is also challenging due to this lack of validated diagnostic approaches, changes in maternal physiology, and the need for intact hemostasis at the time of delivery/epidural analgesia. Prevention requires an optimal balancing of absolute increased bleeding risk from pharmacologic thromboprophylaxis and the absolute benefit of reduced DVT and PE, which, while serious, are relatively uncommon.
Preparing Basic and Translational Grant Proposals: Thoughts from the Trenches
Authors: Molldrem Jeffrey J.
Published: January 2011

Written primarily for first-time applicants, this overview is a collection of tips intended to convey an approach to grant writing based on the experience of the author. Therefore, it is not a comprehensive review and it does not supplant the numerous treatises on grant writing, which cover everything from writing style and grammar to details regarding individual granting mechanisms and agencies. Rather, it is a brief overview of the grant writing process from conception to submission.
Tips for Writing Successful Patient-Oriented Research Career Development Awards
Authors: Lee Stephanie J.
Published: January 2011

Preparing a career development award can be an immensely satisfying experience and a great boost to a research career if successful, or it can seem like a miserable waste of time if unsuccessful. This paper highlights tips for the preparation of patient-oriented career development awards and provides references for grant-writing guidance. Patient-oriented research is defined as “research conducted with human subjects (or on material of human origin such as tissues, specimens and cognitive phenomena) for which an investigator directly interacts with human subjects. This area of research includes: 1) mechanisms of human disease; 2) therapeutic interventions; 3) clinical trials, and; 4) the development of new technologies.”1
Hematology Grants Workshop
Authors: Williams David A.
Published: January 2011

In this yearly update on grant writing, we attempt to provide the attendee/reader with advice from “senior” investigators concerning the application process for external grant funds. While focused particularly on federal (National Institutes of Health, NIH) grants, the advice is generally applicable to any competitive grant-funding mechanism. Drs. Stephanie Lee and Jeffrey Molldrem have provided very thorough advice on clinical and basic grant applications and tips for those early in their careers. The session will include ample time for questions and answers, with key staffers from NIH in attendance.
The Aging Patient with Hemophilia: Complications, Comorbidities, and Management Issues
Authors: Philipp Claire
Published: January 2011

Improvements in hemophilia care and antiviral treatments have resulted in increases in median life expectancy for persons with congenital hemophilia A and B. Currently, 2% of hemophilia A and B patients surveyed in US comprehensive hemophilia treatment centers are 65 years of age or older and 15% are 45 years or older. Many of the complications of hemophilia, including intracranial hemorrhage, joint disease, and inhibitor development, increase with increasing age. Hepatocellular carcinoma and end-stage liver disease are increasing in the older hemophilia population due to infection with hepatitis C (HCV) and HCV/HIV coinfection. Older hemophilia patients also now face the same medical conditions associated with aging in the general population, including cardiovascular disease and cancer. Complex hemostatic management, sometimes in conjunction with antithrombotic management, with extensive cross-specialty clinical and laboratory coordination may be required for the care of the older hemophilia patient. Because elderly hemophilia patients currently represent a small portion of the overall hemophilia population, there is little in the way of clinical data to guide recommendations. Registry databases and cooperative group studies are needed for the development of evidence-based guidelines for the older hemophilia population, which is anticipated to expand in the future.
Alternative Strategies for Gene Therapy of Hemophilia
Authors: Montgomery Robert R. , Shi Qizhen
Published: January 2011

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

Therapeutic 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

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

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

The 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

Stroke 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

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

Conventional 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

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

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

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

Current 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

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

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

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

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.
Monoclonal Gammopathy of Undetermined Significance and Smoldering Myeloma: New Insights into Pathophysiology and Epidemiology
Authors: Landgren Ola
Published: January 2011

Routine screening for monoclonal gammopathy of undetermined significance (MGUS) is not indicated. Despite this fact, MGUS is a common finding in medical practice. Almost all individuals diagnosed with MGUS represent incidental cases diagnosed when physicians order serum protein electrophoresis, immunofixation, or both, as part of the work-up of a number of common symptoms and laboratory abnormalities. In the absence of reliable molecular predictors of outcome, the detection of an early precursor state typically imposes a complex situation for the patient and the responsible physician—usually, it leads to a lot of questions that lack clear answers. In the past years, several novel insights have been gained in the area of multiple myeloma (MM) precursor disease. This review focuses on results from recent investigations and discusses implications for diagnostic work-up, clinical management, and patient counseling. More specifically, it sheds light on the following commonly asked questions by patients and physicians: i) what is the risk of progression from precursor to full-blown MM, and are there ways to risk-stratify patients?; ii) is MM always preceded by a precursor state, and is there anything that could or should be done to delay or prevent progression?; and iii) why do some individuals develop MM precursor diseases, and is there a reason to screen the family?
Telomere Biology and Telomere Diseases: Implications for Practice and Research
Authors: Young Neal S.
Published: January 2011

The recent recognition of genetic defects in telomeres and telomere repair in multiple human diseases has practical implications for hematologists and oncologists and their patients; consequences for future clinical research in hematology and other subspecialties; and even importance in the interpretation of animal experiments involving cell propagation. Telomere diseases include constitutional marrow failure as dyskeratosis congenita, some apparently acquired aplastic anemia, myelodysplasia and acute myeloid leukemia; pulmonary fibrosis; and hepatic nodular regenerative hyperplasia and cirrhosis. Accelerated telomere attrition is a likely pathophysiology of cancer arising from chronic inflammation. Telomerase can be modulated by sex hormones, which may explain the activity of androgens in marrow failure. Measurement of telomere length of peripheral blood leukocytes is a simple screening clinical assay. Detection of a mutation in a patient has implications for therapy, prognosis, monitoring, and genetic counseling. For research in hematology and oncology, telomere biology could be assessed as a risk for secondary malignancies and in graft-versus-host disease, for progression in a variety of blood cancers, and as potentially modifiable by hormone replacement strategies.