bluuebunny/crossref_metadata_2025_split huggingface dataset:
Treatment of hemophagocytic lymphohistiocytosis in adults
Authors: La Rosée Paul 
Published: September 2016

Abstract
Treatment of hemophagocytic lymphohistiocytosis (HLH) has been developed primarily in pediatric centers, where familial HLH (FHL) is the leading cause of HLH in newborns and toddlers. The Histiocyte Society Study Group for HLH developed the HLH-94 and HLH-2004 treatment protocols, and these are frequently also used by centers treating HLH in adults (aHLH). These protocols contain etoposide, dexamethasone, and cyclosporine A; these agents all have strong activity against proliferation of cytotoxic T/NK-cells and macrophages, as well as inhibitory activity against the cytokine storm that induces, and maintains HLH. In children with predominantly hereditary disease, the HLH-94 protocol can be regarded as a “one size fits all” algorithm. HLH in adults is a much more heterogeneous syndrome requiring a more individualized approach depending on the underlying trigger, disease severity and course, as well as genetic background. Additionally, treatment in adults usually needs to be modified in the face of the preceding disease history and comorbidities. Interdisciplinary patient care with rheumatologists, gastroenterologists, neurologists, pediatricians, the transplant team, and pathologists is a prerequisite to successful treatment. The preferred approach should reflect a disease- and risk-adapted treatment that includes rigorous supportive care with continuous reassessment of sequential therapeutic measures. It should be recognized that the algorithm of HLH treatment in adults is based more on expert opinion than on extensive scientific evidence.
Current challenges in diagnostic imaging of venous thromboembolism
Authors: Huisman Menno V. , Klok Frederikus A. 
Published: September 2016

Abstract
Because the clinical diagnosis of deep-vein thrombosis and pulmonary embolism is nonspecific, integrated diagnostic approaches for patients with suspected venous thromboembolism have been developed over the years, involving both non-invasive bedside tools (clinical decision rules and D-dimer blood tests) for patients with low pretest probability and diagnostic techniques (compression ultrasound for deep-vein thrombosis and computed tomography pulmonary angiography for pulmonary embolism) for those with a high pretest probability. This combination has led to standardized diagnostic algorithms with proven safety for excluding venous thrombotic disease. At the same time, it has become apparent that, as a result of the natural history of venous thrombosis, there are special patient populations in which the current standard diagnostic algorithms are not sufficient. In this review, we present 3 evidence-based patient cases to underline recent developments in the imaging diagnosis of venous thromboembolism.
The long and short of it: using the new factor products
Authors: Dunn Amy 
Published: September 2016

Abstract
Hemophilia A (HA) and B (HB) are classified as mild (>5%-40%) moderate (1%-5%) and severe (<1%) disease based on plasma factor activity. Severity of bleeding is commensurate with baseline factor levels in general; however, heterogeneity of bleeding in patients is well described. Recurrent bleeding with painful and disabling musculoskeletal complications is the largest source of morbidity for persons with hemophilia (PWH) but treatment advances through the years has led to improved outcomes. In the early 20th century, only whole blood and fresh frozen plasma (FFP) was available to treat bleeding episodes. In 1959, cryoprecipitate was discovered and became an option for treatment of HA in 1965. In the 1970s plasma fractionation led to the first standard half-life (SHL) concentrates. These products ushered in the use prophylactic therapy to prevent bleeding episodes. However, viral contamination slowed the use of prophylaxis until the 1980s when viral attenuation steps increased the safety of plasma concentrates. In the 1990s recombinant concentrates were developed and prophylactic therapy is increasing widely yet not yet universally used. However even with frequent SHL concentrate infusions outcomes are not optimal as PWH spend the majority of time with factor levels below the normal range and are at increased risk for bleeding. In 2014, the first extended half-life (EHL) products were approved for use and have begun to change the landscape of hemophilia care. Challenges of EHL implementation include patient selection, product selection, dose and schedule of infusions, monitoring for safety, efficacy and outcomes, and managing economic aspects of care.
Evolving diagnostic criteria for multiple myeloma
Authors: Rajkumar S. Vincent 
Published: September 2016

Abstract
Multiple myeloma (MM) is a plasma cell malignancy historically defined by the presence of end-organ damage, specifically, hypercalcemia, renal failure, anemia, and bone lesions (CRAB features) that can be attributed to the neoplastic process. In 2014, the International Myeloma Working Group (IMWG) updated the diagnostic criteria for MM to add specific biomarkers that can be used to make the diagnosis of the disease in patients who did not have CRAB features. In addition, the update allows modern imaging methods including computed tomography (CT) and positron emission tomography-CT to diagnose MM bone disease. These changes enable early diagnosis, and allow the initiation of effective therapy to prevent the development of end-organ damage in patients who are at the highest risk. This article reviews these and several other clarifications and revisions that were made to the diagnostic criteria for MM and related disorders. The updated disease definition for MM also automatically resulted in a revision to the diagnostic criteria for the asymptomatic phase of the disease termed smoldering MM (SMM). Thus the current diagnosis and risk-stratification of SMM is also reviewed in this article. Using specific prognostic factors, it is possible to identify a subset of patients with SMM who have a risk of progression to MM of 25% per year (high-risk SMM). An approach to the management of patients with low- and high-risk SMM is discussed.
Management of hemolytic anemia following allogeneic stem cell transplantation
Authors: Holbro Andreas , Passweg Jakob R. 
Published: September 2016

Abstract
Hemolytic anemia (HA) is a frequent condition with variable pathophysiology. Hematopoietic stem cell transplantation (HSCT) is unique because it is performed across the ABO blood group barrier. Thereby, there is a transfer of plasma, red blood cells, and immunocompetent cells from the donor to the recipient, possibly leading to HA, due to red blood cell incompatibility. The underlying disease, drugs (particularly those used for conditioning and immunosuppressants), infections, graft-versus-host disease, and autoimmune diseases may all contribute to the clinical and laboratory picture of HA. Additionally, transplantation-associated thrombotic microangiopathy (TA-TMA) may occur and is associated with significant morbidity and mortality. This review highlights the current knowledge on HA after allogeneic HSCT, particularly due to ABO incompatibility. We follow the timeline of the transplantation process and discuss investigations, differential diagnosis, and prophylactic measures including graft processing to avoid hemolysis in case of ABO incompatibility. Finally, current therapeutic approaches for both TA-TMA and post-HSCT autoimmune HA, which are associated with high morbidity and mortality, are discussed.
Complement in hemolytic anemia
Authors: Brodsky Robert A. 
Published: September 2016

Abstract
Complement is increasingly being recognized as an important driver of human disease, including many hemolytic anemias. Paroxysmal nocturnal hemoglobinuria (PNH) cells are susceptible to hemolysis because of a loss of the complement regulatory proteins CD59 and CD55. Patients with atypical hemolytic uremic syndrome (aHUS) develop a thrombotic microangiopathy (TMA) that in most cases is attributable to mutations that lead to activation of the alternative pathway of complement. For optimal therapy, it is critical, but often difficult, to distinguish aHUS from other TMAs, such as thrombotic thrombocytopenic purpura; however, novel bioassays are being developed. In cold agglutinin disease (CAD), immunoglobulin M autoantibodies fix complement on the surface of red cells, resulting in extravascular hemolysis by the reticuloendothelial system. Drugs that inhibit complement activation are increasingly being used to treat these diseases. This article discusses the pathophysiology, diagnosis, and therapy for PNH, aHUS, and CAD.
Red blood cell transfusion for hematologic disorders
Authors: Liu Chang , Grossman Brenda J. 
Published: September 2016

AbstractRandomized clinical trials (RCTs) have determined, in surgical and critically ill patients, relatively safe hemoglobin (Hb) thresholds of 7-8 g/dL to guide restrictive transfusion of red blood cells (RBCs). However, in patients with various hematologic disorders, strong evidence in support of such an approach is sparse and the optimal transfusion practice is yet to be defined. This review focuses on RBC transfusion practice in three hematologic diseases and a treatment strategy, including autoimmune hemolytic anemia, thalassemia, myelodysplastic syndrome, and hematopoietic stem cell transplantation. These entities manifest in a broad spectrum of anemia, acute or chronic, in patients with different comorbidities and degrees of transfusion requirement. Thus the nuances in the indications of RBC transfusion and the goals to achieve in these specific situations may have been underappreciated. The limited data available highlight the importance of titrating RBC transfusion based on the clinical context and patient characteristics. Future RCTs are necessary to firmly establish the Hb thresholds associated with improved outcomes relevant to these specific patient populations, which will facilitate the personalized decision-making in RBC transfusion.
Platelet transfusion goals in oncology patients
Authors: Fasano Ross M. , Josephson Cassandra D. 
Published: September 2016

AbstractDespite the advances in platelet component preparation and transfusion support over the years, platelet products remain a limited resource due to their short (5 day) shelf life, and therefore their optimal use in the non-bleeding thrombocytopenic patient continue to draw much attention. There have been a number of national and international guidelines for platelet transfusion therapy in patients with hematologic diseases, some within the last 1-2 years that have incorporated key randomized controlled trials (RCTs) which address issues, such as the optimal platelet dose, the most appropriate threshold for prophylactic platelet transfusions, and whether prophylactic platelet transfusions are superior to therapeutic-only platelet transfusion practices for the prevention life-threatening bleeding in patients with hypoproliferative thrombocytopenia. This review highlights key RCTs and recent systematic reviews focused on optimal platelet transfusion therapy in adult and pediatric patients with hypoproliferative thrombocytopenia secondary to chemotherapy or hematopoietic stem cell transplant (HSCT), discuss how recent innovations in platelet component processing may affect transfusion efficiency, and introduce renewed concepts on adjuvant therapies to prevent bleeding in the hypoproliferative thrombocytopenic patient.
Perinatal thrombosis: implications for mothers and neonates
Authors: O'Brien Sarah H. 
Published: September 2016

AbstractStroke is more likely to occur in the perinatal period than any other time in childhood, and these events can lead to a lifetime of intellectual and motor disabilities, epilepsy, and behavioral challenges. This review describes the epidemiology and natural history of perinatal arterial ischemic stroke (PAIS) and cerebral sinovenous thrombosis (CSVT), risk factors for these complications, recent evidence regarding treatment strategies, and current gaps in knowledge. Existing evidence demonstrates the multifactorial etiology of symptomatic ischemic stroke in neonates, which includes a combination of maternal, delivery, and neonatal factors. The importance of inherited thrombophilia in the pathophysiology and long-term outcomes of perinatal stroke requires additional study. At this time, there is no evidence to support routine extensive thrombophilia screening outside of a research setting. Despite the frequency of perinatal stroke and its association with substantial morbidity, treatment strategies are currently limited, and prevention strategies are nonexistent. Anticoagulation is rarely indicated in PAIS, and more work needs to focus on neuroprotective prevention and alternate treatment strategies. Anticoagulation does appear to be safe in CSVT and may prevent thrombus progression but clinical equipoise remains, and clinical trials are needed to obtain evidence regarding short- and long-term efficacy outcomes.
Peripheral T-cell lymphoma, NOS, and anaplastic large cell lymphoma
Authors: Beaven Anne W. , Diehl Louis F. 
Published: September 2016

AbstractPeripheral T-cell lymphomas (PTCL), with the exception of anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL), have a very poor prognosis. Although current first line chemotherapy continues to be a CHOP-like (cyclophosphamide, doxorubicin, vincristine, prednisone) regimen there is now data suggesting that the addition of etoposide in younger patients improves outcomes. Even for those patients who do have a response to therapy, the risk of relapse remains quite high. Although autologous transplant in first remission is often used, its role as consolidation therapy in first remission remains unclear and may preferentially benefit low-risk patients. In the relapsed setting, major advances have occurred with Food and Drug Administration (FDA) approval of 4 new agents (pralatrexate, romidepsin, belinostat, brentuximab vedotin) for relapsed/refractory PTCL since 2009. These 4 drugs represent the first agents ever approved specifically for this indication. Unfortunately, with the exception of ALCL for which brentuximab vedotin will likely substantially change our approach to treatment, there are still many patients for whom available drugs will not be effective, and it is for these patients that further advances are urgently needed.
Biological and clinical significance of somatic mutations in Langerhans cell histiocytosis and related histiocytic neoplastic disorders
Authors: Allen Carl E. , Parsons D. Williams 
Published: September 2016

AbstractLangerhans cell histiocytosis (LCH), juvenile xanthogranuloma (JXG), and Erdheim–Chester disease (ECD) represent histiocytic disorders with a wide range of clinical manifestations. Until recently, mechanisms of pathogenesis have been speculative and debate has focused on classification of these conditions as reactive versus neoplastic. Genomic studies have been challenged by scarce tissue specimens, as well as heterogeneous nature of the lesions with variable infiltration of pathologic histiocytes. Whole-exome sequencing recently revealed a very low frequency of somatic mutations in LCH, JXG, and ECD compared to other neoplastic disorders. However, at least in the cases of LCH and ECD, there is a very high frequency of activating mutations in MAPK pathway genes, most notably BRAF-V600E, as well as MAP2K1, in LCH and NRAS in ECD. In ECD, recurrent mutations in the PI3K pathway gene PIK3CA have also been described. The heterogeneous clinical manifestations of these disorders may therefore be the cumulative result of activation of MAPK mutations (along with modifying signals from other pathways) at distinct stages of myeloid differentiation. Implications of this model include redefinition of LCH, JXG, and ECD as a group of clinically diverse myeloid neoplastic disorders with a common mechanism of pathogenesis. This model supports refocusing therapeutic strategies for these diseases on a personalized approach based on specific mutations and the cell(s) of origin.
Update in large cell lymphoma: understanding the pathology report
Authors: Hsi Eric D. 
Published: September 2016

AbstractThe diffuse aggressive large B-cell lymphomas are a heterogeneous group of B-cell malignancies. Although many are readily recognized due to characteristic clinical and pathologic features, several problematic areas still exist in diagnosis of these lymphomas due to a variety of reasons that include imprecise or difficult-to-apply diagnostic criteria, gaps in our understanding of lymphoma biology, and limitations in technologies available in the clinical laboratory compared to the research laboratory. This may result in some degree of confusion in the pathology report, particularly if the issues are not clearly explained, leading to frustration or misinterpretation on the part of the reader. In this review, I will discuss the pathologic features of a subset of the WHO 2008 classification diffuse aggressive large B-cell lymphomas, focusing on areas in which difficulties exist in diagnosis and/or biomarker marker assessment. A deeper understanding of the issues and areas of uncertainty due to limitations in our knowledge about the biology of these diseases should lead to better communication between pathologists and clinicians.
Using the pathology report in initial treatment decisions for diffuse large B-cell lymphoma: time for a precision medicine approach
Authors: Friedberg Jonathan W. 
Published: September 2016

Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non Hodgkin lymphoma in the Western world, and is potentially curable with standard R-CHOP chemoimmunotherapy. Historically, clinical risk assessments provided prognostic information, but did not define treatment approach. We are now in an era where the heterogeneity of DLBCL is defined genetically and molecularly, and rational subset-specific therapeutic targets are guiding clinical trials. Primary mediastinal DLBCL is a unique clinicopathologic entity, and alternatives to R-CHOP may confer superior outcome. Rearrangement of the myc oncogene occurs in ∼10% of patients with DLBCL, and confers a very poor prognosis with standard R-CHOP, particularly when there is concomitant rearrangement of bcl-2, a condition referred to as “double-hit” DLBCL. A larger subset of DLBCL demonstrates overexpression of both myc and bcl-2 by immunohistochemistry. Cell of origin, determined by gene expression analysis, immunohistochemistry algorithms, or a novel Lymph2Cx platform, provides prognostic information, and guides therapeutic decisions in both relapsed and de novo disease. This article will define specific subsets of DLBCL and provide subtype-specific treatment options, including novel approaches under investigation. Understanding these key features of the pathology report, and limitations of these assays defining subsets of DLBCL, allows for an evolving precision medicine approach to this disease.
Syndromes of thrombotic microangiopathy associated with pregnancy
Authors: George James N. , Nester Carla M. , McIntosh Jennifer J. 
Published: September 2016

Abstract
When a pregnant or postpartum woman presents with sudden and severe microangiopathic hemolytic anemia (MAHA) and thrombocytopenia, three syndromes that require urgent care must be considered: (1) preeclampsia with severe features/hemolysis, elevated liver function tests, low platelets (PE/HELLP) syndrome; (2) thrombotic thrombocytopenic purpura (TTP); and (3) complement-mediated thrombotic microangiopathy (C-TMA; also referred to as atypical hemolytic–uremic syndrome). The distinction among these three syndromes is often unclear because they share multiple clinical features. Overlap between PE/HELLP syndrome and the other two syndromes is also apparent from the fact that pregnancy can be a trigger for both TTP and C-TMA both before and after delivery and also the increased frequency of PE/HELLP syndrome in women who have recovered from TTP. When diagnostic criteria for PE/HELLP syndrome are present, management of hypertension and delivery is curative. Absence of improvement or actual progression of MAHA, thrombocytopenia, and kidney function abnormalities after delivery requires consideration of TTP and C-TMA. Minimal kidney involvement with severe thrombocytopenia suggests TTP and the need for treatment with plasma exchange; progressive kidney injury (in the absence of a cause for acute tubular necrosis) suggests C-TMA and the need for anti-complement treatment. We describe how we use these criteria to evaluate and manage pregnant/postpartum women with MAHA and thrombocytopenia.
What is the role of autologous transplant for lymphoma in the current era?
Authors: Stiff Patrick 
Published: September 2016

Abstract
The role of autologous hematopoietic stem cell transplantation (ASCT) in the management of non-Hodgkin's lymphoma (NHL) is evolving, in the era of novel agents. Multiple histologies and remission stages have been impacted with changing outcomes. In the 1990s, ASCT could cure 50% of relapsed chemosensitive aggressive NHL; now the percentage maybe as low as 20% for patients relapsing within 1 year of completing rituximab-containing induction. Yet recent trials have clarified the value of first remission ASCT for high-grade NHL, the utility of augmented preparative regimens, the efficacy of ASCT in primary CNS lymphoma and in the elderly and analyses have defined strategies to reduce transplant related myeloid malignancies. In addition, optimizing nontransplant induction therapy for mantle cell and double-hit NHL is leading to improved outcomes and a re-examination of the use of ASCT in first complete remission. Caution is needed, however, as delaying transplants may mean that patients will need more morbid allogeneic transplants to achieve long-term control of refractory disease. As an alternative, maintenance therapy trials to improve ASCT outcome in high-risk patients are starting, based on the efficacy of lenolidomide and brentuximab in myeloma and Hodgkin's lymphoma, respectively. In addition, efforts to define early high-risk patients by minimal residual disease (MRD) assessments and genetic profiling, are beginning even for those with “indolent” phenotypes not currently autotransplanted. These efforts should not only refine but also enhance the value of early potentially curative ASCT, especially if novel agents only delay but do not prevent relapse for patients with NHL.
Iron deficiency: new insights into diagnosis and treatment
Authors: Camaschella Clara 
Published: September 2016

Abstract
Iron deficiency and iron deficiency anemia are common conditions worldwide affecting especially children and young women. In developing countries, iron deficiency is caused by poor iron intake and/or parasitic infection, whereas vegetarian dietary choices, poor iron absorption, and chronic blood loss are common causes in high-income countries. Erythropoiesis stimulating agents can result in functional iron deficiency for erythropoiesis even when stores are iron-replete. Diagnosis of iron deficiency is straightforward, except when it occurs in the context of inflammatory disorders. Oral iron salts correct absolute iron deficiency in most patients, because low hepcidin levels facilitate iron absorption. Unfortunately frequent side effects limit oral iron efficacy. Intravenous iron is increasingly utilized, because currently available preparations allow rapid normalization of total body iron even with a single infusion and are effective also in functional iron deficiency and in iron deficiency associated with inflammatory disorders. The evidence is accumulating that these preparations are safe and effective. However, long-term safety issues of high doses of iron need to be further explored.