bluuebunny/crossref_metadata_2025_split huggingface dataset:
Accelerating safe drug development: an ideal approach to approval
Authors: Grever Michael R. 
Published: December 2013

Abstract
Although enormous progress in therapeutic research has improved the lives of patients with hematologic malignancies, these earlier achievements resulted from strategic combinations of agents with unique mechanisms of action and nonoverlapping toxicities. Continued investment in the modern era of drug discovery and development will focus on targeted therapies. Targeting of specific molecular pathways is expected to achieve effective tumor cell reduction with less overall toxicity. The translational processes involved in moving novel therapeutic strategies from the laboratory toward the clinic require close monitoring. The efforts in both cancer drug discovery and development will require extensive collaboration among basic scientists, clinical investigators, and regulatory scientists. The transition from older methods of therapeutic research will require laboratory support to define eligible patients based upon their pretreatment profile. The principles of preclinical drug development based upon decades of experience in predicting toxicity and designing therapeutic strategies are still needed to insure that safety is a high priority. The opportunities for developing novel targeted combination therapies in uniquely profiled patients will hopefully enable successful breakthroughs. Several concrete examples of exciting new agents are discussed here. Defining the predicted mechanism of resistance to these new targeted agents will enable investigators to subsequently design strategies to circumvent resistance with effective combinations. Drug discovery and development are complex and expensive, so efficiency and cooperation in task completion must be tracked.
Is anti-D immunoglobulin still a frontline treatment option for immune thrombocytopenia?
Authors: Despotovic Jenny M. , Neunert Cindy E. 
Published: December 2013

Abstract
A 5-year-old boy presents with platelet count of 2 × 109/L and clinical and laboratory evidence of immune thrombocytopenia. He has epistaxis and oral mucosal bleeding. Complete blood count reveals isolated thrombocytopenia without any decline in hemoglobin and he is Rh+. You are asked if anti-D immunoglobulin is an appropriate initial therapy for this child given the 2010 Food and Drug Administration “black-box” warning.
Current consideration and management of disseminated intravascular coagulation
Authors: Toh Cheng Hock , Alhamdi Yasir 
Published: December 2013

AbstractDisseminated intravascular coagulation (DIC) is a devastating clinical condition that is characterized by the loss of normal hemostatic control in response to sustained and systemic cell injury. The inciting injury may be from infection, trauma, or malignancy, but the consequent pathophysiology is multifactorial involving intertwined feedback loops between the coagulant, immune, and inflammatory pathways. Central to this is thrombin generation, but the ubiquitous nature of its in vivo functional consequences can make it difficult to dissect away the separate but overlapping components to the clinical problem. Therefore, early recognition and resolution of the precipitating events leading to DIC remains the central tenet to clinical care. This article refreshes our conceptual understanding of DIC pathogenesis and draws in recent advances in the cycle of cell death caused by extracellular nuclear proteins. It also aims to delineate recognition of response pathways that can be predominantly procoagulant or profibrinolytic to enable a more personalized and evidence-based approach to be delivered to the patient with DIC.
Opening up drug development to everyone
Authors: Adelman Burt 
Published: December 2013

Abstract
Effective drug therapies are a cornerstone of medical practice. The path from drug discovery to approval is expensive and commonly associated with failure. The cost of drug development exceeds 800 million dollars per product. Late failure due to lack of clinical efficacy is a common cause of high costs. Recent attempts to improve the process of drug development involve the formation of public–private partnerships, which are facilitating the creation of new collaborations among corporate and nonprofit entities to find solutions that will accelerate innovative drug discovery.
ABCs of genomics
Authors: Bohlander Stefan K. 
Published: December 2013

Abstract
Our genome, the 6 billion bp of DNA that contain the blueprint of a human being, has become the focus of intense interest in medicine in the past two decades. Two developments have contributed to this situation: (1) the genetic basis of more and more diseases has been discovered, especially of malignant diseases, and (2) at the same time, our abilities to analyze our genome have increased exponentially through technological breakthroughs. We can expect genomics to become ever more relevant for day-to-day treatment decisions and patient management. It is therefore of great importance for physicians, especially those who are treating patients with malignant diseases, to become familiar with our genome and the technologies that are currently available for genomics analysis. This review provides a brief overview of the organization of our genome, high-throughput sequence analysis methods, and the analysis of leukemia genomes using next-generation sequencing (NGS) technologies.
Genomic stratification for the treatment of lymphomas
Authors: Dave Sandeep S. 
Published: December 2013

Abstract
The application of high-throughput genomic approaches in lymphomas has generated a wealth of data regarding the molecular underpinnings of these cancers. In this review, key findings from recent studies are discussed, as well as the genetic heterogeneity that underlies common lymphomas including diffuse large B-cell lymphoma, Burkitt lymphoma, and chronic lymphocytic leukemia, and the implications for identifying new therapeutic opportunities and personalized medicine.
Natural killer cells and regulatory T cells: how to manipulate a graft for optimal GVL
Authors: Verneris Michael R. 
Published: December 2013

Abstract
Two of the major complications that limit the efficacy of allogeneic hematopoietic cell transplantation (allo-HCT) are disease relapse and GVHD. Due to their rapid recovery early after allo-HCT and their ability to kill malignant targets without prior exposure, natural killer (NK) cells have been considered one of the main effector cells that mediate early GVL reactions. Conversely, regulatory T ells (Tregs) have proven to be critical in facilitating self-tolerance. Both murine and human studies have demonstrated a significant role for Tregs in the modulation of GVHD after allo-HCT. This article reviews the mechanisms of how these 2 cell types carry out these functions, focusing on the post-allo-HCT period. Surprisingly, relatively few studies have addressed how Tregs and NK cells interact with one another and whether these interactions are antagonistic. Although preclinical studies suggest active cross-talk between NK cells and Tregs, early clinical studies have not shown a detrimental impact of Treg therapy on relapse. Despite this, interruption of tolerogenic signals may enhance the efficacy of NK effector functions. Methods to transiently impair Treg functions and augment NK cell alloreactivity will be discussed.
Genetic association studies in β-hemoglobinopathies
Authors: Thein Swee Lay 
Published: December 2013

AbstractCharacterization of the molecular basis of the β-thalassemias and sickle cell disease (SCD) clearly showed that individuals with the same β-globin genotypes can have extremely diverse clinical severity. Two key modifiers, an innate ability to produce fetal hemoglobin and coinheritance of α-thalassemia, both derived from family and population studies, affect the pathophysiology of both disorders at the primary level. In the past 2 decades, scientific research had applied genetic approaches to identify additional genetic modifiers. The review summarizes recent genetic studies and key genetic modifiers identified and traces the story of fetal hemoglobin genetics, which has led to an emerging network of globin gene regulation. The discoveries have provided insights on new targets for therapeutic intervention and raise possibilities of developing fetal hemoglobin predictive diagnostics for predicting disease severity in the newborn and for integration into prenatal diagnosis to better inform genetic counseling.
Pathogenesis and clinical implications of HIV-related anemia in 2013
Authors: Redig Amanda J. , Berliner Nancy 
Published: December 2013

AbstractAnemia is a common feature of HIV-related disease and has been uniformly demonstrated to be an independent predictor of morbidity and mortality. Although anemia often responds to combination antiretroviral therapy, many patients remain anemic despite therapy and such persistent anemia continues to negatively affect prognosis regardless of drug response. Anemia is also a common feature of normal aging. We postulate that the pathophysiology of anemia in HIV, especially that which persists in the face of combination antiretroviral therapy, is a reflection of underlying proinflammatory pathways that are also thought to contribute to anemia in the elderly, as well as other age-related chronic diseases such as cardiovascular disease and chronic obstructive pulmonary disease. This suggests that HIV induces inflammatory pathways that are associated with a pattern of accelerated aging and that anemia is a biomarker of these processes. A better understanding of the pathophysiology of HIV-related anemia may provide important entry points for improving the chronic manifestations of HIV-related disease.
Transplantation in HIV-infected subjects: is cure possible?
Authors: Zaia John A. , Forman Stephen J. 
Published: December 2013

Abstract
With the advent of effective antiretroviral therapy, the treatment of patients with HIV-related malignancies, especially lymphoma, has greatly improved, yielding results comparable to those seen in patients with lymphoma unrelated to HIV. The platform of transplantation of hematopoietic stem cells has facilitated studies of genetically modified stem cells engineered to express antiretroviral genes to resist infection by the HIV virus, testing the concept that engraftment of these cells will lead to HIV resistance and elimination of the reservoir of virus in the body. Results in patients with HIV and lymphoma have now led to studies that will test these principles in HIV patients without concomitant malignancy. In addition, in a patient with HIV and acute myeloid leukemia, the success of an allogeneic transplantation from an unrelated donor carrying a mutation in the CCR5 genes has demonstrated that, in principle, such an approach could also lead to cure of patients with HIV. Case studies in HIV patients with leukemia undergoing allogeneic transplantation also suggest that there may be a therapeutic effect on the HIV reservoir that could alter the natural history of HIV in the allogeneic setting.
Novel therapy for Hodgkin lymphoma
Authors: Batlevi Connie Lee , Younes Anas 
Published: December 2013

AbstractThe treatment of Hodgkin lymphoma (HL) relies on multimodality treatment with standard chemotherapy, radiation therapy, and autologous or allogeneic stem cell transplantation in cases of relapsed disease. Genomic advances in HL provided insights into deregulation of key nodal signaling pathways, including the PI3K, NF-κB, and JAK/STAT pathways, which are amenable to small-molecule targeting. Understanding how HL cells interact and depend on their microenvironment for survival signals and immune protection may uncover other such pathways. Small-molecule targeting has the potential to dramatically improve treatment outcomes, especially in patients with highly refractory disease and those with poor tolerance to existing chemotherapies. As novel therapies continue to be developed for HL, the challenge will be to address the needs of high-risk groups, reduce long-term therapy-related morbidity, position current established treatments with novel therapies, and concurrently develop biomarkers to aid in patient selection. Brentuximab vedotin, which was approved in 2011, is already shifting the treatment paradigm of HL. Undoubtedly, other novel therapeutics in the pipeline will affect positively the landscape of treatment in HL.
Lymphocyte-predominant Hodgkin lymphoma: what is the optimal treatment?
Authors: Fanale Michelle 
Published: December 2013

AbstractNodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a unique diagnostic entity, with only ∼ 500 new cases in the United States per year with a similar infrequent incidence worldwide. NLPHL also has distinctive pathobiology and clinical characteristics compared with the more common classical Hodgkin lymphoma (cHL), including CD20 positivity of the pathognomic lymphocytic and histiocytic cells and an overall more indolent course with a higher likelihood of delayed relapses. Given the limited numbers of prospective NLPHL-focused trials, management algorithms historically have typically been centered on retrospective data with guidelines often adopted from cHL and indolent B-cell lymphoma treatment approaches. Key recent publications have delineated that NLPHL has a higher level of pathological overlap with cHL and the aggressive B-cell lymphomas than with indolent B-cell lymphomas. Over the past decade, there has been a series of NLPHL publications that evaluated the role of rituximab in the frontline and relapsed setting, described the relative incidence of transformation to aggressive B-cell lymphomas, weighed the benefit of addition of chemotherapy to radiation treatment for patients with early-stage disease, considered what should be the preferred chemotherapy regimen for advanced-stage disease, and even assessed the potential role of autologous stem cell transplantation for the management of relapsed disease. General themes within the consensus guidelines include the role for radiation treatment as a monotherapy for early-stage disease, the value of large B-cell lymphoma–directed regimens for transformed disease, the utility of rituximab for treatment of relapsed disease, and, in the pediatric setting, the role of surgical management alone for patients with early-stage disease.
Evidence-based approach to treatment of febrile neutropenia in hematologic malignancies
Authors: Gea-Banacloche Juan 
Published: December 2013

Abstract
Applying the principles of evidence-based medicine to febrile neutropenia (FN) results in a more limited set of practices than expected. Hundreds of studies over the last 4 decades have produced evidence to support the following: (1) risk stratification allows the identification of a subset of patients who may be safely managed as outpatients given the right health care environment; (2) antibacterial prophylaxis for high-risk patients who remain neutropenic for ≥ 7 days prevents infections and decreases mortality; (3) the empirical management of febrile neutropenia with a single antipseudomonal beta-lactam results in the same outcome and less toxicity than combination therapy using aminoglycosides; (4) vancomycin should not be used routinely empirically either as part of the initial regimen or for persistent fever, but rather should be added when a pathogen that requires its use is isolated; (5) empirical antifungal therapy should be added after 4 days of persistent fever in patients at high risk for invasive fungal infection (IFI); the details of the characterization as high risk and the choice of agent remain debatable; and (6) preemptive antifungal therapy in which the initiation of antifungals is postponed and triggered by the presence, in addition to fever, of other clinical findings, computed tomography (CT) results, and serological tests for fungal infection is an acceptable strategy in a subset of patients. Many practical management questions remain unaddressed.
Sickle cell disease pain management and the medical home
Authors: Raphael Jean L. , Oyeku Suzette O. 
Published: December 2013

AbstractPain is the most common cause for hospitalization and acute morbidity in sickle cell disease (SCD). The consequences of SCD-related pain are substantial, affecting both the individual and the health care system. The emergence of the patient-centered medical home (PCMH) provides new opportunities to align efforts to improve SCD management with innovative and potentially cost-effective models of patient-centered care. The Department of Health and Human Services has designated SCD as a priority area with emphasis on creating PCMHs for affected patients. The question for patients, clinicians, scientists, and policy-makers is how the PCMH can be designed to address pain, the hallmark feature of SCD. This article provides a framework of pain management within the PCMH model. We present an overview of pain and pain management in SCD, gaps in pain management, and current care models used by patients and discuss core PCMH concepts and multidisciplinary team–based PCMH care strategies for SCD pain management.
Pros and cons of new oral anticoagulants
Authors: Bauer Kenneth A. 
Published: December 2013

Abstract
The availability of new oral anticoagulants (NOACs) targeting either thrombin (dabigatran etexilate) or factor Xa (rivaroxaban and apixaban) for the prevention and treatment of thrombosis has been highly anticipated. NOACs have major pharmacologic advantages over vitamin K antagonists (eg, warfarin), including rapid onset/offset of action, few drug interactions, and predictable pharmacokinetics, eliminating the requirement for regular coagulation monitoring. Regulatory agencies have approved several NOACs for specific indications based on the results of clinical trials demonstrating efficacy and safety that are at least as good, if not better, than warfarin (for stroke prevention in atrial fibrillation and treatment and secondary prevention of venous thromboembolism) or low-molecular-weight heparin, which is injectable (for initial treatment of venous thromboembolism and thromboprophylaxis in patients undergoing hip or knee arthroplasty). However, the adoption of this new therapeutic class into clinical practice has been slower than expected due to several factors including concerns regarding medication adherence without laboratory monitoring, uncertainty about dosing in some patient populations (eg, renal dysfunction, marked extremes of body weight), and higher drug costs compared with warfarin. Other issues are the current absence of specific antidotes for NOACs and assays to measure drug levels at most centers. The indications for NOACs on the market will expand and at least one additional agent (edoxaban) will likely gain approval within the next 2 years. As practitioners gain familiarity with the drugs and healthcare systems adapt to their use, NOAC use will increase substantially over time. Warfarin, however, will continue to be an appropriate anticoagulant choice for many patients.
Risk assessment for recurrence and optimal agents for extended treatment of venous thromboembolism
Authors: Agnelli Giancarlo , Becattini Cecilia 
Published: December 2013

Abstract
Venous thromboembolism (VTE) has a variable recurrence rate after the discontinuation of anticoagulant treatment. Therefore, the duration of anticoagulation therapy after a first VTE should be tailored to the estimated risk for recurrence. Anticoagulant therapy should be discontinued after the initial 3 to 6 months in those patients who had the first episode in association with temporary risk factors. The duration of anticoagulant therapy in patients who had a first episode of cancer-associated VTE should be reassessed over time based on the persistence of cancer and anticancer therapy. After 3 to 6 months of anticoagulant treatment for VTE, patients with a first unprovoked event and an estimated low risk for bleeding complications should be evaluated for indefinite treatment on an individualized basis. New oral anticoagulants have been evaluated for the extended treatment of VTE. Large phase 3 studies have shown that dabigatran, rivaroxaban, and apixaban are effective and safe in this indication. These agents do not require monitoring for dose adjustment and could make extended treatment more feasible and acceptable to patients.
What is the role of prophylaxis in the improvement of health-related quality of life of patients with hemophilia?
Authors: Buchbinder David , Ragni Margaret V. 
Published: December 2013

AbstractA 32-year-old male with severe hemophilia presents for his annual evaluation. He has a history of multiple joint bleeds that he has always treated on-demand, that is, after they occur. You have recommended prophylaxis, that is, preventively, before they occur, to decrease his episodes of bleeding; however, he had been reluctant to comply in the past. He is having difficulty keeping up at work because of interruptions, pain, and lost time at work. He is willing to consider a trial of prophylaxis. You discuss the impact of hemophilia on his health-related quality of life (HRQOL) and consider measuring his HRQOL over time using a generic measure of HRQOL to determine whether prophylaxis will reduce interruptions, pain, and lost time from work and improve his HRQOL.
JAK inhibition in the myeloproliferative neoplasms: lessons learned from the bench and bedside
Authors: Gotlib Jason 
Published: December 2013

AbstractThe discovery of the JAK2 V617F mutation in the classic BCR-ABL1–negative myeloproliferative neoplasms in 2005 catalyzed a burst of research efforts that have culminated in substantial dividends for patients. Beyond JAK2 V617F, a more detailed picture of the pathobiologic basis for activated JAK-STAT signaling has emerged. In some patients with myelofibrosis (MF), next-generation sequencing technologies have revealed a complex clonal architecture affecting both genetic and epigenetic regulators of cell growth and differentiation. Although these bench-top findings have informed the clinical development of JAK inhibitors in MF, they have also provided scientific context for some of their limitations. The JAK1/JAK2 inhibitor ruxolitinib is approved for treatment of MF in North America and Europe and other lead JAK inhibitors discussed herein (fedratinib [SAR302503], momelotinib [CYT387], and pacritinib [SB1518]), have entered advanced phases of trial investigation. Uniformly, these agents share the ability to reduce spleen size and symptom burden. A major challenge for practitioners is how to optimize dosing of these agents to secure clinically relevant and durable benefits while minimizing myelosuppression. Suboptimal responses have spurred a “return to the bench” to characterize the basis for disease persistence and to inform new avenues of drug therapy.
Beyond JAK inhibitor therapy in myelofibrosis
Authors: Odenike Olatoyosi 
Published: December 2013

AbstractMyelofibrosis (MF), including primary MF, postpolycythemia vera MF, and postessential thrombocythemia MF, is a clonal stem cell disorder characterized by BM fibrosis, extramedullary hematopoiesis, and a variable propensity to transform into acute leukemia. Allogeneic stem cell transplantation is the only known cure for MF, but its applicability is limited by the advanced age of most patients and by comorbid conditions. In the past decade, there has been an explosion of information on the molecular-genetic features associated with these diseases, fueled recently by the discovery of the JAK2V617F mutation. The development of JAK inhibitors has represented a significant therapeutic advance for these diseases; however, their use in MF has not yet been associated with eradication or a significant suppression of the malignant clone. In this era, much remains to be understood about MF, but it is likely that the identification of key pathogenetic drivers of the disease, coupled with the availability of novel molecularly targeted agents, will result in the discovery of new agents that significantly alter the natural history of the disease. This review focuses on recent and ongoing efforts in the development of novel agents in MF that go beyond the field of JAK inhibitors.