bluuebunny/crossref_metadata_2025 huggingface dataset:
Utilization of mouse models to decipher natural killer cell biology and potential clinical applications
Authors: Sungur Can M. , Murphy William J.
Published: December 2013

Natural killer (NK) cells represent a key component of innate immunity. The utility of mouse models to recapitulate the human immune response has been a matter of ongoing debate, especially with regard to NK cells. However, mouse models of NK cells have provided significant advancements in our understanding of the biology of the cells that bridge these species. Initial characterization of NK cell activity was in mouse hematopoietic stem cell transplantation models. Recent findings include uncovering functionally disparate subsets of NK cells based on unique inhibitory receptor expression patterns, the existence of memory-like NK cells, and immunoregulatory NK cells that affect hematopoiesis and T-cell function. In addition, the biology of these cells with regard to MHC-binding receptors that affect NK cell subset maturation and function in the context of licensing, the importance of cytokines such as IL-15 in their development and maintenance, and evidence of NK exhaustion have been initially studied in mice. Many of these findings have been validated in clinical studies and demonstrate the significant wealth of knowledge that can be obtained by mouse models. However, it is important to understand the limitations and conditions of the mouse models, particularly when studying NK cells in hematopoietic stem cell transplantation and cancer.
Bringing natural killer cells to the clinic: ex vivo manipulation
Authors: Childs Richard W. , Berg Maria
Published: December 2013

Recently, there has been a substantial gain in our understanding of the role that natural killer (NK) cells play in mediating innate host immune responses against viruses and cancer. Although NK cells have long been known to be capable of killing cancer cells independently of antigen recognition, the full therapeutic potential of NK cell–based immunotherapy has yet to be realized. Here we review novel methods to activate and expand human NK cells ex vivo for adoptive transfer in humans, focusing on the important phenotypic and functional differences observed among freshly isolated, cytokine activated, and ex vivo–expanded NK populations.
Accelerating safe drug development: an ideal approach to approval
Authors: Grever Michael R.
Published: December 2013

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

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

Disseminated 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

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

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

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

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

Characterization 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

Anemia 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

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

The 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

Nodular 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

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

Pain 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

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

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

A 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

The 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

Myelofibrosis (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.
Allogeneic transplantation for AML and MDS: GVL versus GVHD and disease recurrence
Authors: van Besien Koen
Published: December 2013

Allogeneic transplantation constitutes curative treatment for acute myeloid leukemia and myelodysplastic syndrome. Its therapeutic effects are to a large extent mediated by GVL effects, but partially offset by treatment-related mortality and loss of quality of life caused by acute and chronic GVHD. Although severe acute and chronic GVHD are associated with a reduction in relapse risk, they are not associated with improved survival. Recent efforts to modulate the GVL-GVH balance include novel methods of in vitro or in vivo T-cell depletion that are associated with a minimal impact on rates of disease recurrence and a dramatically decreased risk for GVHD. Donor selection algorithms may also have a significant impact on transplantation outcomes. Low-expression HLA alleles, particularly HLA-DP, should be incorporated in selection of adult unrelated donors. Evolving data suggest that KIR typing may also be important. High-resolution HLA typing and the importance of fetal-maternal interactions in umbilical cord blood transplantation are also briefly discussed. A combination of donor selection strategies and GVHD prophylaxis methods will favorably affect long-term outcomes and create an environment suitable for effective posttransplantation interventions.
The use of platelet-rich plasma in the nonsurgical management of sports injuries: hype or hope?
Authors: Harmon Kimberly G. , Rao Ashwin L.
Published: December 2013

Interest in platelet-rich plasma (PRP) has skyrocketed over the last decade, with a growing body of research contributing to both excitement and skepticism regarding its use. Despite mixed opinions in the medical field, interest from the public has fueled increased utilization of PRP for musculoskeletal conditions, particularly those that are difficult to treat such as chronic, degenerative tendinopathy and osteoarthritis. PRP's reputation as a “natural healer” and stories in the lay press featuring the use of PRP by professional athletes and celebrities has created a lucrative market for PRP even absent insurance reimbursement, casting further doubt regarding motivation for use by some practitioners. Research of PRP is clouded by the fact that PRP is a heterogeneous term representing a variety of different platelet preparations and there are many variables in technique and postprocedure rehabilitation, all of which may have significant effects on outcome. This article discusses definitions and classification of PRP, reviews rationale and evidence for use of PRP in chronic tendon injuries and osteoarthritis, and looks at future directions.
Pharmacological methods to reduce disease recurrence
Authors: Craddock Charles
Published: December 2013

Allogeneic stem cell transplantation is an increasingly important treatment option in patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Although there has been substantial progress in reducing transplantation-related mortality (TRM), little progress has been made in reducing the risk of disease relapse, which continues to represent the major cause of treatment failure in patients allografted for AML and MDS. Experience with myeloablative conditioning regimens has demonstrated that, although intensification of the preparative regimen reduces relapse risk, any survival benefit is blunted by a concomitant increase in TRM. A similar inverse correlation between relapse risk and TRM is observed in patients allografted using a reduced-intensity conditioning regimen. However, the markedly lower toxicity of such regimens has permitted the design of novel conditioning strategies aimed at maximizing antitumor activity without excessive transplant toxicity. Coupled with recent advances in drug delivery and design, this has allowed the development of a spectrum of new conditioning regimens in patients with high-risk AML and MDS. At the same time, the optimization of a graft-versus-leukemia (GVL) effect by minimizing posttransplantation immunosuppression, with or without the infusion of donor lymphocytes, is essential if the risk of disease relapse is to be reduced. Recently, the delivery of adjunctive posttransplantation therapies has emerged as a promising method of augmenting antileukemic activity, either through a direct antitumor activity or consequent upon pharmacological manipulation of the alloreactive response. Taken together these advances present a realistic possibility of delivering improved outcome in patients allografted for high-risk AML or MDS.
Fresh versus old blood: are there differences and do they matter?
Authors: Zimring James C.
Published: December 2013

The medical effects of transfusing stored RBCs is an area of significant concern that has received substantial attention in recent years. Retrospective trials show all possible outcomes, including sequelae from transfusing older RBCs, no difference between older and fresher RBCs, and a benefit to older RBCs. Several prospective clinical trials are under way to further investigate potential untoward effects of stored RBCs. Thus far, the issue of potential sequelae from transfusing stored RBCs remains a highly controversial issue. However, what is not controversial is that RBC storage is an unnatural state during which a series of substantial changes take place to the stored RBCs. These changes result in the formation of cellular and chemical entities known to have biological activities in other settings, giving rise to several distinct hypotheses by which stored RBCs may alter recipient biology. Herein, the clinical background and basic science of RBC storage are reviewed, with a particular focus on factors that may complicate hypothesis testing and obfuscate underlying biologies. The complexity of the RBC storage lesion, donor-to-donor variation, and the diversity of recipient pathophysiologies remain a challenge to prospective trials assessing the safety of stored RBCs.
Resuscitation of trauma-induced coagulopathy
Authors: Hess John R.
Published: December 2013

For 30 years, the Advanced Trauma Life Support course of the American College of Surgeons taught that coagulopathy was a late consequence of resuscitation of injury. The recognition of trauma-induced coagulopathy overturns that medical myth and creates a rationale for procoagulant resuscitation. Analysis of the composition of currently available blood components allows prediction of the upper limits of achievable coagulation activity, keeping in mind that oxygen transport must be maintained simultaneously. RBCs, plasma, and platelets given in a 1:1:1 unit ratio results in a hematocrit of 29%, plasma concentration of 62%, and platelet count of 90 000 in the administered resuscitation fluid. Additional amounts of any 1 component dilute the other 2 and any other fluids given dilute all 3. In vivo recovery of stored RBCs is ∼ 90% and that of platelets ∼ 60% at the mean age at which such products are given to trauma patients. This means that useful concentrations of the administered products are a hematocrit of 26%, a plasma coagulation factor activity of 62% equivalent to an international normalized ratio of ∼ 1.2, and a platelet count of 54 000. This means there is essentially no good way to give blood products for resuscitation of trauma-induced coagulopathy other than 1:1:1. Because 50% of trauma patients admitted alive to an academic-level 1 trauma center who will die of uncontrolled hemorrhage will be dead in 2 hours, the trauma system must be prepared to deliver plasma- and platelet-based resuscitation at all times.
Heparin-induced thrombocytopenia
Authors: Lee Grace M. , Arepally Gowthami M.
Published: December 2013

Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder caused by antibodies that recognize complexes of platelet factor 4 (PF4) and heparin. HIT is frequently considered in the differential diagnosis of thrombocytopenia occurring in patients on heparin therapy. HIT is a challenging diagnosis because of routine heparin use in hospitalized patients, the common occurrence of thrombocytopenia, and high rates of anti-PF4/heparin seroconversions in patients treated with heparin. Our diagnostic approach to HIT is presented here, underscoring critical elements of clinical and laboratory evaluation.
Should the presence of an antiphospholipid antibody affect the duration of anticoagulant treatment in patients with venous thromboembolism?
Authors: Garcia David A. , Lim Wendy
Published: December 2013

A 44-year-old otherwise healthy woman has completed 3 months of anticoagulation therapy for a first episode of unprovoked pulmonary embolism. At the time of diagnosis and before the initiation of anticoagulation, she was found to have an elevated IgG anticardiolipin antibody (ACLA), which was measured at 42 IgG phospholipid (GPL) units (reference range, < 15 GPL units) with negative lupus anticoagulant (LAC) testing. Should this laboratory finding affect the recommended duration of anticoagulant therapy?
Cancer-associated thrombosis
Authors: Connolly Gregory C. , Francis Charles W.
Published: December 2013

Cancer-associated thrombosis accounts for almost one-fifth of all cases of venous thromboembolism (VTE) and is a leading cause of death, morbidity, delays in care, and increased costs. Our understanding of risk factors for cancer-associated thrombosis has expanded in recent years, and investigators have begun to use biomarkers and clinical prediction models to identify those cancer patients at greatest risk for VTE. The Khorana Risk Model, which is based on easily obtained biomarkers and clinical factors, has now been validated in several studies. Recent clinical trials of prophylaxis and treatment of VTE in cancer patients are reviewed here. In addition, consensus guidelines and expert opinion regarding management of VTE in specific challenging situations are presented.
Older patients/older donors: choosing wisely
Authors: Artz Andrew S.
Published: December 2013

Two lingering problems regarding transplantation in older adults have been how to select patients appropriately and whether to use older sibling donors. Allogeneic hematopoietic cell transplantation (HCT) of older patients may result in long-term survival due to GVL, but the data remain observational and mostly restricted to those 50 to 69 years of age. Patients with excellent performance status and low comorbidity have the best long-term survival after HCT. Novel measures of health status such as self-report or performance-based functional measures allow “staging the age” and may inform candidacy for less robust patients. Older matched sibling donors should be preferred over matched unrelated donors (MUDs) because outcomes are equivalent to superior for matched sibling donors compared with MUD. However, MUDs also achieve acceptable outcomes and long-term disease control. An alternative donor can be considered based on institutional protocols and expertise. Very limited information is available in patients or related donors 70 years of age and older. Future efforts to more completely characterize patient health status before transplantation will allow better application of HCT in older adults.
Current concepts in the pathophysiology and treatment of aplastic anemia
Authors: Young Neal S.
Published: December 2013

Historically viewed in isolation as an odd, rare, and invariably fatal blood disease, aplastic anemia is now of substantial interest for its immune pathophysiology, its relationship to constitutional BM failure syndromes and leukemia, and the success of both stem cell transplantation and immunosuppressive therapies in dramatically improving survival of patients. Once relegated to a few presentations in the red cell and anemia sessions of the ASH, the Society now sponsors multiple simultaneous sessions and plenary and scientific committee presentations on these topics. This update emphasizes developments in our understanding of immune mechanisms and hematopoietic stem cell biology and new clinical approaches to stem cell stimulation as a therapy, alone and in combination with conventional suppression of the aberrant immune system.
Management of the refractory aplastic anemia patient: what are the options?
Authors: Marsh Judith C. W. , Kulasekararaj Austin G.
Published: December 2013

Refractory aplastic anemia (AA) is defined as a lack of response to first-line immunosuppressive therapy (IST) with antithymocyte globulin and cyclosporin and is manifested as persistence of severe cytopenias at 6 months after IST. Although supportive care is critical for AA patients, it is of paramount importance for refractory disease in view of the longer duration of pancytopenia and susceptibility to life-threatening infections due to IST. Improvements in supportive care have largely contributed to better outcome over the past 2 decades, with 5-year overall survival reaching 57% during 2002 to 2008 for patients with AA unresponsive to initial IST. Exclusion of hypocellular myelodysplastic syndrome and constitutional BM failure masquerading as apparent idiopathic AA should be done in conjunction with centers of excellence. Hematopoietic stem cell transplantation is indicated if refractory AA patients are fit and have a suitably matched donor, either a sibling (> 40-50 years) or unrelated donor. Patients lacking a fully matched donor should be considered for a second course of antithymocyte globulin plus cyclosporin, although response in the refractory setting is only ∼ 30% to 35%. Response may also occur with alemtuzumab or the thrombopoietin mimetic eltrombopag in refractory AA. The emerging data for alternate donor (cord or haploidentical) transplantation in AA has provided additional therapeutic choices to consider in refractory disease.
Cellular determinants for preclinical activity of a novel CD33/CD3 bispecific T-cell engager (BiTE) antibody, AMG 330, against human AML
Authors: Laszlo George S. , Gudgeon Chelsea J. , Harrington Kimberly H. , Dell’Aringa Justine , Newhall Kathryn J. , Means Gary D. , Sinclair Angus M. , Kischel Roman , Frankel Stanley R. , Walter Roland B.
Published: December 2013

Key Points

AMG 330 cytotoxicity against AML cells is proportional to the level of CD33 expression but is not affected by ABC transporter activity. AMG 330 cytotoxicity is amenable to modulation and augmentation by clinically available drugs such as histone deacetylase or DNA methyltransferase I inhibitors.
Genetic heterogeneity of asthma phenotypes identified by a clustering approach
Authors: Siroux Valérie , González Juan R. , Bouzigon Emmanuelle , Curjuric Ivan , Boudier Anne , Imboden Medea , Anto Josep Maria , Gut Ivo , Jarvis Deborah , Lathrop Mark , Omenaas Ernst Reidar , Pin Isabelle , Wjst Mathias , Demenais Florence , Probst-Hensch Nicole , Kogevinas Manolis , Kauffmann Francine
Published: December 2013

The aim of the study was to identify genetic variants associated with refined asthma phenotypes enabling multiple features of the disease to be taken into account.

Latent class analysis (LCA) was applied in 3001 adults ever having asthma recruited in the frame of three epidemiological surveys (the European Community Respiratory Health Survey (ECRHS), the Swiss Study on Air Pollution and Lung Disease in Adults (SAPALDIA) and the Epidemiological Study on the Genetics and Environment of Asthma (EGEA)). 14 personal and phenotypic characteristics, gathered from questionnaires and clinical examination, were used. A genome-wide association study was conducted for each LCA-derived asthma phenotype, compared to subjects without asthma (n=3474).

The LCA identified four adult asthma phenotypes, mainly characterised by disease activity, age of asthma onset and atopic status. Associations of genome-wide significance (p<1.25×10−7) were observed between “active adult-onset nonallergic asthma” and rs9851461 flankingCD200(3q13.2) and between “inactive/mild nonallergic asthma” and rs2579931 flankingGRIK2(6q16.3). Borderline significant results (2.5×10−7<p<8.2×10−7) were observed between three single nucleotide polymorphisms (SNPs) in theALCAMregion (3q13.11) and “active adult-onset nonallergic asthma”. These results were consistent across studies. 15 SNPs identified in previous genome-wide association studies of asthma have been replicated with at least one asthma phenotype, most of them with the “active allergic asthma” phenotype.

Our results provide evidence that a better understanding of asthma phenotypic heterogeneity helps to disentangle the genetic heterogeneity of asthma.
A 2-year randomised placebo-controlled trial of doxycycline for lymphangioleiomyomatosis
Authors: Chang William Y.C. , Cane Jennifer L. , Kumaran Maruti , Lewis Sarah , Tattersfield Anne E. , Johnson Simon R.
Published: December 2013

Lymphangioleiomyomatosis (LAM) is characterised by lung cysts and airflow obstruction. Matrix metalloproteinases have been implicated in lung destruction in LAM. We performed a randomised, double-blind trial, comparing the matrix metalloproteinases inhibitor doxycycline with placebo on the progression of LAM.

23 females with LAM were randomised to doxycycline 100 mg daily for 3 months followed by 200 mg daily for 21 months, or matched placebo. Lung function, exercise capacity, quality of life and matrix metalloproteinases levels were measured.

21 patients completed 6 months of treatment, 17 completed 1 year of treatment and 15 completed 2 years of treatment. Eight withdrew from the trial due, four due to a pneumothorax and four because of other reasons. The mean±sddecline in FEV1, the primary endpoint, did not differ between the groups being -90±154 mL·year−1in the placebo group and -123±246 mL·year−1in the doxycycline group (difference -32.5, 95% CI -213–148; p=0.35). Doxycycline had no effect upon vital capacity, gas transfer, shuttle walk distance or quality of life. Urine matrix metalloproteinases-9 measurements were lower with doxycycline treatment (p=0.03).

Although with limited numbers we cannot completely exclude an effect of doxycycline, the lack of effect on any outcome makes it unlikely that doxycycline has a useful effect in LAM.
Arterial stiffness in patients with COPD: the role of systemic inflammation and the effects of pulmonary rehabilitation
Authors: Vanfleteren Lowie E.G.W. , Spruit Martijn A. , Groenen Miriam T.J. , Bruijnzeel Piet L.B. , Taib Ziad , Rutten Erica P.A. , Op ‘t Roodt Jos , Akkermans Marco A. , Wouters Emiel F.M. , Franssen Frits M.E.
Published: December 2013

Clear evidence for an association between systemic inflammation and increased arterial stiffness in patients with chronic obstructive pulmonary disease (COPD) is lacking. Moreover, the effects of pulmonary rehabilitation on arterial stiffness are not well studied.

We aimed to 1) confirm increased arterial stiffness in COPD; 2) evaluate its correlates including systemic inflammation; and 3) study whether or not it is influenced by pulmonary rehabilitation.

Aortic pulse-wave velocity (APWV) was determined in 168 healthy volunteers, and APWV and inflammatory markers were determined in 162 COPD patients during baseline evaluation of a pulmonary rehabilitation programme. A complete post-pulmonary rehabilitation dataset was collected in 129 patients.

It was found that APWV was increased in COPD patients when compared with controls, blood pressure and age predicted baseline APWV, and systemic inflammatory markers were not independently related to APWV. Although baseline APWV was predictive for the change in APWV after pulmonary rehabilitation (r= -0.77), on average APWV did not change (10.7±2.7versus10.9±2.5 m·s−1; p=0.339).

Arterial stiffness in COPD is not related to systemic inflammation and does not respond to state-of-the-art pulmonary rehabilitation. These results emphasise the complexity of cardiovascular risk and its management in COPD.
On fixed point theorems involving altering distances in Menger probabilistic metric spaces
Authors: Došenović Tatjana , Kumam Poom , Gopal Dhananjay , Patel Deepesh Kumar , Takači Aleksandar
Published: December 2013

In this paper, we show by means of an example that the results of Babačev (Appl. Anal. Discrete Math. 6:257-264, 2012) do not hold for the class of t-norms

T
≤

T
p

. Further, we prove a fixed point theorem for quasi-type contraction involving altering distance functions which is weaker than that proposed by Babačev but for any continuous t-norm in a complete Menger space.

MSC:47H10, 54H25.
Sample size calculation based on exact test for assessing differential expression analysis in RNA-seq data
Authors: Li Chung-I , Su Pei-Fang , Shyr Yu
Published: December 2013

Background

Sample size calculation is an important issue in the experimental design of biomedical research. For RNA-seq experiments, the sample size calculation method based on the Poisson model has been proposed; however, when there are biological replicates, RNA-seq data could exhibit variation significantly greater than the mean (i.e. over-dispersion). The Poisson model cannot appropriately model the over-dispersion, and in such cases, the negative binomial model has been used as a natural extension of the Poisson model. Because the field currently lacks a sample size calculation method based on the negative binomial model for assessing differential expression analysis of RNA-seq data, we propose a method to calculate the sample size.

Results

We propose a sample size calculation method based on the exact test for assessing differential expression analysis of RNA-seq data.

Conclusions

The proposed sample size calculation method is straightforward and not computationally intensive. Simulation studies to evaluate the performance of the proposed sample size method are presented; the results indicate our method works well, with achievement of desired power.