bluuebunny/crossref_metadata_2025_split huggingface dataset:
Educational Session: Managing Chronic Myeloid Leukemia as a Chronic Disease
Authors: Hochhaus Andreas 
Published: December 2011

Abstract
Elucidation of the pathogenesis of chronic myeloid leukemia (CML) and the introduction of tyrosine kinase inhibitors (TKIs) has transformed this disease from being invariably fatal to being the type of leukemia with the best prognosis. Median survival associated with CML is estimated at > 20 years. Nevertheless, blast crisis occurs at an incidence of 1%-2% per year, and once this has occurred, treatment options are limited and survival is short. Due to the overall therapeutic success, the prevalence of CML is gradually increasing. The optimal management of this disease includes access to modern therapies and standardized surveillance methods for all patients, which will certainly create challenges. Furthermore, all available TKIs show mild but frequent side effects that may require symptomatic therapy. Adherence to therapy is the key prerequisite for efficacy of the drugs and for long-term success. Comprehensive information on the nature of the disease and the need for the continuous treatment using the appropriate dosages and timely information on efficacy data are key factors for optimal compliance. Standardized laboratory methods are required to provide optimal surveillance according to current recommendations. CML occurs in all age groups. Despite a median age of 55-60 years, particular challenges are the management of the disease in children, young women with the wish to get pregnant, and older patients. The main challenges in the long-term management of CML patients are discussed in this review.
Minimal Residual Disease and Discontinuation of Therapy in Chronic Myeloid Leukemia: Can We Aim at a Cure?
Authors: Melo Junia V. , Ross David M. 
Published: December 2011

Abstract
Patients with chronic myeloid leukemia (CML) who have achieved a complete molecular response (CMR) defined by no detectable BCR-ABL mRNA on imatinib (IM) treatment often ask whether it is necessary for treatment to continue. We now know that approximately 40% of patients with a stable CMR for at least 2 years are able to stop IM treatment and remain in molecular remission for at least 2 years. This exciting observation has raised hopes that many patients can be cured of CML without the need for transplantation and its attendant risks. One might argue that for many patients maintenance therapy with IM or an alternative kinase inhibitor is so well tolerated that there is no imperative to stop treatment; however, chronic medical therapy may be associated with impaired quality of life and reduced compliance. Inferences about the biology of CML in patients responding to kinase inhibitors can be drawn from clinical experience, molecular monitoring data, and experimental observations. We summarize this information herein, and propose 3 possible pathways to “cure” of CML by kinase inhibitors: stem-cell depletion, stem-cell exhaustion, and immunological control.
Heparin-Induced Thrombocytopenia Screening and Management in Pediatric Patients
Authors: Takemoto Clifford M. , Streiff Michael B. 
Published: December 2011

Abstract
The diagnosis and management of heparin-induced thrombocytopenia (HIT) in pediatric patients poses significant challenges. The cardinal findings in HIT, thrombocytopenia and thrombosis with heparin exposure, are seen commonly in critically ill children, but are most often secondary to etiologies other than HIT. However, without prompt diagnosis, discontinuation of heparin, and treatment with an alternative anticoagulant such as a direct thrombin inhibitor (DTI), HIT can result in life- and limb-threatening thrombotic complications. Conversely, DTIs are associated with higher bleeding risks than heparin in adults and their anticoagulant effects are not rapidly reversible; furthermore, the experience with their use in pediatrics is limited. Whereas immunoassays are widely available to aid in diagnosis, they carry a significant false positive rate. Age-dependent differences in the coagulation and immune system may potentially affect manifestations of HIT in children, but have not been extensively examined. In this chapter, diagnostic approaches and management strategies based on a synthesis of the available pediatric studies and adult literature on HIT are discussed.
Bleeding and Clotting Disorders in Pediatric Liver Disease
Authors: Wicklund Brian M. 
Published: December 2011

Abstract
The coagulopathy of liver disease in pediatric patients presents an unusual set of challenges. Little pediatric data have been published, so this review is based largely on adult studies. There is a precarious balance between deficiencies of clotting factors and anticoagulation factors in liver disease that result in abnormal prothrombin time (PT) and activated partial thromboplastin time (aPTT) tests that would suggest a bleeding tendency, yet the patients can form a clot and are at risk of thromboembolic disease. Attention has centered on thromboelastography and thrombin-generation assays to clarify the patient's ability to control bleeding, but these tests are not routinely available to many treating physicians.
Stem Cell Transplantation for Multiple Myeloma: Current and Future Status
Authors: Giralt Sergio 
Published: December 2011

Abstract
High-dose melphalan with autologous stem cell support has been an integral part of myeloma therapy for more than 25 years, either as salvage therapy or as consolidation of an initial remission. Although multiple phase 3 trials have demonstrated that this therapy results in higher response rates and longer remission times than conventional chemotherapy, the use of thalidomide, lenalidomide, and bortezomib as induction therapy has limited the clinical relevance of these trials. Moreover, ongoing trials have shown that initial induction therapy may affect transplantation outcome, and that long-term disease control can be achieved in a substantial number of patients with a variety of posttransplantation maintenance therapies. This article summarizes the results of ongoing and recently published clinical trials and describes how they have affected current transplantation recommendations.
Myelodysplastic/Myeloproliferative Neoplasms
Authors: Cazzola Mario , Malcovati Luca , Invernizzi Rosangela 
Published: December 2011

AbstractAccording to the World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues, myelodysplastic/myeloproliferative neoplasms are clonal myeloid neoplasms that have some clinical, laboratory, or morphologic findings that support a diagnosis of myelodysplastic syndrome, and other findings that are more consistent with myeloproliferative neoplasms. These disorders include chronic myelomonocytic leukemia, atypical chronic myeloid leukemia (BCR-ABL1 negative), juvenile myelomonocytic leukemia, and myelodysplastic/myeloproliferative neoplasms, unclassifiable. The best characterized of these latter unclassifiable conditions is the provisional entity defined as refractory anemia with ring sideroblasts associated with marked thrombocytosis. This article focuses on myelodysplastic/myeloproliferative neoplasms of adulthood, with particular emphasis on chronic myelomonocytic leukemia and refractory anemia with ring sideroblasts associated with marked thrombocytosis. Recent studies have partly clarified the molecular basis of these disorders, laying the groundwork for the development of molecular diagnostic and prognostic tools. It is hoped that these advances will soon translate into improved therapeutic approaches.
Posttransplantation Vaccination: Concepts Today and on the Horizon
Authors: Rezvani Katayoun 
Published: December 2011

AbstractAllogeneic hematopoietic stem cell transplantation (allogeneic HSCT) remains a curative treatment for hematological malignancies resistant to other treatment approaches through the unique GVL effect. However, relapse remains a major cause of treatment failure after allogeneic HSCT for patients with high-risk hematological malignancies. Further improvements in exploiting the GVL effect to prevent relapse in high-risk leukemias while minimizing toxicity have focused on the use of targeted antileukemic immunotherapy. These strategies include methods to boost the GVL effect with leukemia vaccines or the adoptive transfer of leukemia-specific lymphocytes. Vaccines can be classified as those against defined antigens such as minor histocompatibility antigens (mHags) or leukemia-associated antigens (PR1, WT1, and BCR-ABL) and those that have broad “antileukemic” activity such as engineered irradiated leukemia cells or leukemia-derived dendritic cells (DCs). The unique posttransplantation milieu, which is characterized by lymphopenia, regulatory T-cell depletion, and the release of growth factors, provides a unique opportunity for effective antitumor immunotherapy and augmenting specific GVL responses. This review focuses on approaches to enhancimg the GVL response by combining allogeneic HSCT with vaccination.
Tyrosine Kinase Inhibitor Use in Pediatric Philadelphia Chromosome–Positive Acute Lymphoblastic Anemia
Authors: Hunger Stephen P. 
Published: December 2011

Abstract
Until recently, pediatric Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) was associated with an extremely poor outcome when treated with chemotherapy alone, and only modest survival benefits were obtained with the widespread use of hematopoietic stem cell transplantation (HSCT). The development of first-generation (imatinib) and second-generation (dasatinib and nilotinib) tyrosine kinase inhibitors (TKIs) that target the BCR-ABL1 fusion protein produced by the Ph chromosome revolutionized the treatment of chronic myelogenous leukemia (CML). The Children's Oncology Group (COG) AALL0031 trial showed that the addition of imatinib to intensive chemotherapy did not cause increased toxicity and resulted in 3-year event-free survival rates that were more than double those of historical control data from the pre-imatinib era. These findings create a new paradigm for integrating molecularly targeted agents with conventional chemotherapy and call for a reassessment of the routine use of HSCT for children and adolescents with Ph+ ALL. Second-generation TKIs have theoretical advantages over imatinib, and are now being tested in Ph+ ALL. The focus of contemporary trials is to define the optimal use of chemotherapy, HSCT, and TKI in Ph+ ALL. In the coming years, it is anticipated that additional agents will become available to potentiate TKI therapy and/or circumvent TKI resistance in Ph+ ALL. Recent genomic studies have identified a subtype of high-risk pediatric B-cell-precursor ALL with a gene-expression profile similar to that of Ph+ ALL, suggestive of active kinase signaling. Many of these Ph-like ALL cases harbor chromosome rearrangements and mutations that dysregulate cytokine receptor and kinase signaling, and these leukemias may also be candidates for TKI therapy.
Pulmonary Hypertension, Tricuspid Regurgitant Velocity Screening, and the Nitric Oxide Pathway
Authors: Hassell Kathryn L. 
Published: December 2011

AbstractChronic pulmonary complications, including pulmonary hypertension (PH), are common in sickle cell disease (SCD), especially in adults with sickle cell anemia (SCA). The underlying pathophysiology is complex and variable, involving multiple biological systems. Recent emphasis has been placed on the pleotropic biological factor nitric oxide (NO). An elevated tricuspid regurgitant velocity (TRV) appears to have limitations in specificity in SCA, but may indicate the presence of PH, a diagnosis confirmed by right heart catheterization. TRV has been used in recent clinical trials to identify or define subjects with PH for enrollment into PH-specific interventions; these include sildenafil, which enhances NO-induced vasorelaxation. Results from a controlled trial show no benefit and an unexpected increase in adverse events, emphasizing the biological complexities of SCA. Management remains principally supportive, includes recognition and treatment of comorbidities, and may incorporate individualized PH-specific strategies (despite recent trials) based on appropriate diagnostic testing. Ultimately, therapy is likely to be multimodal and tailored to the processes identified to be the most contributory in a given individual. Based on the relative prevalence of the conditions, routine screening for asthma in children with SCD and by Doppler echocardiography to measure TRV as an initial screen for PH in adults with SCA may be warranted. Data are limited regarding the clinical utility of screening in other forms of SCD and the pediatric population. This article offers an individual perspective on practical and challenging clinical considerations.
Novel Approaches to the Treatment of Acute Myeloid Leukemia
Authors: Roboz Gail J. 
Published: December 2011

Abstract
Approximately 12 000 adults are diagnosed with acute myeloid leukemia (AML) in the United States annually, the majority of whom die from their disease. The mainstay of initial treatment, cytosine arabinoside (ara-C) combined with an anthracycline, was developed nearly 40 years ago and remains the worldwide standard of care. Advances in genomics technologies have identified AML as a genetically heterogeneous disease, and many patients can now be categorized into clinicopathologic subgroups on the basis of their underlying molecular genetic defects. It is hoped that enhanced specificity of diagnostic classification will result in more effective application of targeted agents and the ability to create individualized treatment strategies. This review describes the current treatment standards for induction, consolidation, and stem cell transplantation; special considerations in the management of older AML patients; novel agents; emerging data on the detection and management of minimal residual disease (MRD); and strategies to improve the design and implementation of AML clinical trials.
Primary Prophylaxis in Sickle Cell Disease: Is It Feasible? Is It Effective?
Authors: Thompson Alexis A. 
Published: December 2011

AbstractConsideration of primary prophylaxis to prevent complications of sickle cell disease (SCD) requires a clear understanding of the earliest manifestations of SCD-related organ injury, a reliable clinical or laboratory tool to detect organ dysfunction, and evidence that an intervention instituted in the presymptomatic state can mitigate disease progression. This review examines the pathophysiology of SCD in organs that may be potential targets for intervention, our current capacity to evaluate early SCD manifestations, results of clinical trials, and opportunities for future interventions.
Vascular Effects of the Red Blood Cell Storage Lesion
Authors: Roback John D. 
Published: December 2011

Abstract
Transfusion of RBCs is often clinically necessary—and life-saving—for anemic patients. RBCs can be stored for up to 42 days between the time of donation and the time of transfusion. For many years, investigators have studied the biochemical changes that occur in RBCs stored before transfusion (the RBC “storage lesion”). More recently, clinical studies have suggested that RBC units stored for long periods (often described as > 14-21 days) may mediate adverse effects in the recipient, leading to morbidity and mortality. Unfortunately, these effects are difficult to identify and study because there are no agreed-upon mechanisms for these adverse events and few good assays to study them in individual transfusion recipients. We have proposed the hypothesis of insufficient NO bioavailability (INOBA) to explain the adverse events associated with transfusion of older RBC units. INOBA postulates that the combination of impaired NO production and increased NO scavenging by stored RBCs, together with reduced NO synthesis by dysfunctional endothelial cells, collectively reduce NO levels below a critical threshold in vascular beds. In this situation, inappropriate vasoconstriction occurs, leading to reduced blood flow and insufficient O2 delivery to end organs. If confirmed, the INOBA hypothesis may lead to improved methods for blood storage and collection, as well as new screening and matching tools for blood donors and transfusion recipients.
Dyskeratosis Congenita
Authors: Dokal Inderjeet 
Published: December 2011

Abstract
Dyskeratosis congenita (DC) is a multisystem inherited syndrome exhibiting marked clinical and genetic heterogeneity. In its classic form, it is characterized by mucocutaneous abnormalities, BM failure, and a predisposition to cancer. BM failure is the principal cause of premature mortality. Studies over the last 15 years have led to significant advances, with 8 DC genes (DKC1, TERC, TERT, NOP10, NHP2, TIN2, C16orf57, and TCAB1) having been characterized. Seven of these are important in telomere maintenance either because they encode components of the telomerase enzyme complex (DKC1, TERC, TERT, NOP10, NHP2, and TCAB1) or the shelterin complex (TINF2). DC is therefore principally a disease of defective telomere maintenance and patients usually have very short telomeres. The genetic advances have led to the unification of DC with several other disorders, including the severe multisystem disorders Hoyeraal-Hreidarsson and Revesz syndromes, as well as a subset of patients with aplastic anemia, myelodysplasia, leukemia, and idiopathic pulmonary fibrosis. This wide spectrum of diseases ranging from classic DC to aplastic anemia can be regarded as disorders of defective telomere maintenance—“the telomereopathies.” These advances have increased our understanding of normal hematopoiesis and highlighted the important role of telomerase and telomeres in human biology. They are also facilitating the diagnosis (especially when presentation is atypical) and management of DC.
Congenital Sideroblastic Anemias: Iron and Heme Lost in Mitochondrial Translation
Authors: Fleming Mark D. 
Published: December 2011

AbstractThe congenital sideroblastic anemias (CSAs) are an uncommon, diverse class of inherited hematopoietic disorders characterized by pathological deposition of iron in the mitochondria of erythroid precursors. In recent years, the genetic causes of several clinically distinctive forms of CSA have been elucidated, which has revealed common themes in their pathogenesis. In particular, most, if not all, can be attributed to disordered mitochondrial heme synthesis, iron-sulfur cluster biogenesis, or pathways related to mitochondrial protein synthesis. This review summarizes the clinical features, molecular genetics, and pathophysiology of each of the CSAs in the context of these pathways.
Immunomodulating Drugs in Myelodysplastic Syndromes
Authors: Adès Lionel , Fenaux Pierre 
Published: December 2011

Abstract
Based on immune mechanisms that appear to play an important role in the pathophysiology of at least part of the lower-risk myelodysplastic syndrome (MDS), the immunomodulating drug (IMID) thalidomide and its derivative lenalidomide (LEN) have been used in MDS, principally in lower-risk MDS. LEN has become the first-line US Food and Drug Administration (FDA)–approved treatment for lower-risk MDS with 5q deletion (del5q), in which its main mechanism of action is probably a direct cytotoxic activity on the del5q clone. This possibly specific effect is currently being investigated in higher-risk MDS—and even acute myeloid leukemia (AML)—with del5q, but LEN has also demonstrated some efficacy in MDS and AML without del5q. Thalidomide also has some activity in lower-risk MDS without del5q, but its side effects limit its practical use in these patients.
Diagnosis and Management of Aplastic Anemia
Authors: Guinan Eva C. 
Published: December 2011

Abstract
Aplastic anemia remains a diagnosis of exclusion. Our ability to reliably diagnose, and therefore exclude, a variety of inherited or acquired diseases with similar phenotypes has improved markedly. An efficient diagnostic plan is important because time from diagnosis to treatment is related to outcome regardless of the therapeutic option chosen. HSCT remains the mainstay of therapy for those with matched sibling donors, and results have improved even further in recent years. For those without a sibling donor, the high response and overall survival rates of combined immunosuppressive therapy (IST) have proven robust. Nonetheless, incomplete response, relapse, and progression to myelodysplasia/leukemia have more clearly emerged as significant long-term issues. Improvements in outcome of alternative donor transplantation and the use of established and novel immunosuppressive agents provide multiple alternatives for treating refractory or relapsed patients. Best practices in this regard are not yet clearly established and may vary by a variety of demographic and treatment-specific factors. Regardless of the type of therapeutic approach, patients require ongoing monitoring for occurrence of disease and/or therapy-related side effects.
Therapy for Aplastic Anemia
Authors: DeZern Amy E. , Guinan Eva C. 
Published: December 2011

Abstract
A 24-year-old man from Ecuador presents to your clinic with dyspnea on exertion, bruising, and petechiae. He is noted to be pancytopenic with ANC 430, hemoglobin 7.4 g/dL (reticulocyte count 0.9%), and platelets 18 000. His BM biopsy is hypocellular for age. Ultimately, he is diagnosed with severe aplastic anemia. He is the only child of 2 South American parents without any matches in the unrelated donor registry, including cord blood. He is red cell– and platelet transfusion–dependent. He has been recommended therapy with antithymocyte globulin and cyclosporine but declined it. He seeks recommendations about new alternatives to this regimen to improve his chance of response.
Comparative incidence of a first thrombotic event in purely obstetric antiphospholipid syndrome with pregnancy loss: the NOH-APS observational study
Authors: Gris Jean-Christophe , Bouvier Sylvie , Molinari Nicolas , Galanaud Jean-Philippe , Cochery-Nouvellon Éva , Mercier Érik , Fabbro-Peray Pascale , Balducchi Jean-Pierre , Marès Pierre , Quéré Isabelle , Dauzat Michel 
Published: December 2011

AbstractThe incidence of thrombosis in the purely obstetric form of antiphospholipid syndrome is uncertain. We performed a 10-year observational study of 1592 nonthrombotic women who had experienced 3 consecutive spontaneous abortions before the 10th week of gestation or 1 fetal death at or beyond the 10th week of gestation. We compared the frequencies of thrombotic events among women positive for antiphospholipid Abs (n = 517), women carrying the F5 6025 or F2 rs1799963 polymorphism (n = 279), and women with negative thrombophilia screening results (n = 796). The annual rates of deep vein thrombosis (1.46%; range, 1.15%-1.82%), pulmonary embolism (0.43%; range, 0.26%-0.66%), superficial vein thrombosis (0.44%; range, 0.28%-0.68%), and cerebrovascular events (0.32%; range, 0.18%-0.53%) were significantly higher in aPLAbs women than in the other groups despite low-dose aspirin primary prophylaxis. Women carrying 1 of the 2 polymorphisms did not experience more thrombotic events than women who screened negative for thrombophilia. Lupus anticoagulant was a risk factor for unprovoked proximal and distal deep and superficial vein thrombosis and women in the upper quartile of lupus anticoagulant activity had the highest risk. Despite data suggesting that aPLAbs may induce pregnancy loss through nonthrombotic mechanisms, women with purely obstetric antiphospholipid syndrome are at risk for thrombotic complications.