bluuebunny/crossref_metadata_2025 huggingface dataset:
Oral Health Knowledge, Attitudes, and Perceptions of Pregnant Kuwaiti Women
Authors: Al Khamis S. , Asimakopoulou K. , Newton J.T. , Daly B.
Published: September 2016

Good oral hygiene is known to prevent maternal gingivitis, but little is known about Kuwaiti pregnant women’s understanding and beliefs about maintaining and improving oral health during pregnancy. This qualitative study investigated perceptions, beliefs, and attitudes about oral health among Kuwaiti pregnant women and explored beliefs about maintaining and improving oral health during pregnancy. In-depth one-to-one interviews were conducted with a purposive sample of 19 Kuwaiti pregnant women across 7 government primary health care centers in Kuwait. A topic guide framed the questions, which explored pregnancy, oral health, oral health and pregnancy, oral health knowledge, and oral health behaviors. All interviews were digitally recorded, transcribed verbatim, and analyzed by thematic analysis. The key themes emerging from the data related to low oral health knowledge, unhelpful cultural beliefs concerning oral health during pregnancy, and lack of awareness about the effect of pregnancy on oral health. Pregnant women lacked motivation to seek dental care even when they considered dental treatment safe during pregnancy. Dentists’ purported incorrect beliefs about providing dental treatment to pregnant women and the women’s lack of motivation were identified as barriers to accessing oral health care and seeking oral health knowledge. Pregnant women in this study had not received the necessary oral health information to undertake appropriate oral health behaviors. Cultural beliefs and practices about oral health were identified that need to be tackled to improve and maintain positive oral health behaviors during pregnancy. Behavioral interventions must acknowledge the cultural sensitivity around beliefs during pregnancy and, as a first step, focus on correcting oral health knowledge among Kuwaiti pregnant women.

Knowledge Transfer Statement: The results of this qualitative study can be used by oral health care workers and researchers to plan and design more targeted dental health education interventions with pregnant women. The information in this study might be helpful to public health decision makers to make more appropriate decisions about implementing dental health education with pregnant women.
Diffusion and retention behaviour of Cs in illite-added compacted montmorillonite
Authors: Ishidera Takamitsu , Kurosawa Seiichi , Hayashi Masanori , Uchikoshi Keiji , Beppu Hikari
Published: September 2016

Compacted bentonite is to be used as a component of an engineered barrier system to retard the migration of radionuclides in the geological disposal of radioactive waste. In such an environment, montmorillonite in compacted bentonite might be altered to illite due to the hydrothermal reactions caused by the decay heat of radionuclides. In the present study, the diffusion and retention behaviour of Cs in compacted montmorillonite containing illitewas investigated using through-diffusion experiments. The experimental results showed that the flux of Cs attributed to the surface diffusion was independent of the sorption of Cs on illite, indicating that the Cs sorbed on illite was immobile or considerably less mobile than the Cs sorbed on montmorillonite. Consequently, the illite content in compacted bentonite is expected to enhance the sorption capacity of Cs without causing surface diffusion.
Effect of layer charge on the crystalline swelling of Na+, K+ and Ca2+ montmorillonites: DFT and molecular dynamics studies
Authors: Seppälä Anniina , Puhakka Eini , Olin Markus
Published: September 2016

The swelling and cation exchange properties of montmorillonite are fundamental in a wide range of applications ranging from nanocomposites to catalytic cracking of hydrocarbons. The swelling results from several factors and, though widely studied, information on the effects of a single factor at a time is lacking. In this study, density functional theory (DFT) calculations were used to obtain atomic-level information on the swelling of montmorillonite. Molecular dynamics (MD) was used to investigate the swelling properties of montmorillonites with different layer charges and interlayer cationic compositions. Molecular dynamics calculations, with CLAYFF force field, consider three layer charges (−1.0, −0.66 and −0.5 e per unit cell) arising from octahedral substitutions and interlayer counterions of Na, K and Ca. The swelling curves obtained showed that smaller layer charge results in greater swelling but the type of the interlayer cation also has an effect. The DFT calculations were also seen to predict larger d values than MD. The formation of 1, 2 and 3 water molecular layers in the interlayer spaces was observed. Finally, the data from MD calculations were used to predict the selfdiffusion coefficients of interlayer water and cations in different montmorillonites and in general the coefficient increased with increasing water content and with decreasing layer charge.
Game of clones: the genomic evolution of severe congenital neutropenia
Authors: Touw Ivo P.
Published: September 2016

Severe congenital neutropenia (SCN) is a genetically heterogeneous condition of bone marrow failure usually diagnosed in early childhood and characterized by a chronic and severe shortage of neutrophils. It is now well-established that mutations in HAX1 and ELANE (and more rarely in other genes) are the genetic cause of SCN. In contrast, it has remained unclear how these mutations affect neutrophil development. Innovative models based on induced pluripotent stem cell technology are being explored to address this issue. These days, most SCN patients receive life-long treatment with granulocyte colony-stimulating factor (G-CSF, CSF3). CSF3 therapy has greatly improved the life expectancy of SCN patients, but also unveiled a high frequency of progression toward myelodysplastic syndrome (MDS) and therapy refractory acute myeloid leukemia (AML). Expansion of hematopoietic clones with acquired mutations in the gene encoding the G-CSF receptor (CSF3R) is regularly seen in SCN patients and AML usually descends from one of these CSF3R mutant clones. These findings raised the questions how CSF3R mutations affect CSF3 responses of myeloid progenitors, how they contribute to the pre-leukemic state of SCN, and which additional events are responsible for progression to leukemia. The vast (sub)clonal heterogeneity of AML and the presence of AML-associated mutations in normally aged hematopoietic clones make it often difficult to determine which mutations are responsible for the leukemic process. Leukemia predisposition syndromes such as SCN are unique disease models to identify the sequential acquisition of these mutations and to interrogate how they contribute to clonal selection and leukemic evolution.
Lymphocytosis, lymphadenopathy: benign or malignant?
Authors: Winter Jane N. , Peterson LoAnn C.
Published: September 2016

The increasing use of immunophenotypic and molecular analysis in the routine evaluation of patients with lymphocytosis, lymphadenopathy, or other hematologic disorders has led to the identification of unexpected small clonal lymphoid populations. These clones, sometimes with disease-specific markers, such as the t(14;18), are especially challenging for the clinician because of their unknown biologic potential and uncertain clinical behavior. Study of these early lymphoid lesions is providing important clues to the process of lymphomagenesis, and may provide the rationale for preemptive therapy in the future. More and more, the hematologist/oncologist is consulted regarding otherwise healthy individuals with lymphadenopathy and/or lymphocytosis, and pathology reports that confound the referring internist or surgeon. The report does not name a malignant lymphoproliferative disorder, but is not completely “normal”. Does the patient have a benign or malignant condition? How should they be evaluated? Is treatment indicated? These patients prove challenging for the consulting hematologist as well as the referring physician. In this review, we will focus on some of these scenarios and attempt to provide guidance for their management.
Monitoring and reversal of direct oral anticoagulants
Authors: Cuker Adam , Siegal Deborah
Published: September 2016

Although the direct oral anticoagulants (DOACs) do not require routine monitoring and reduce bleeding compared with warfarin, there are special circumstances in which laboratory measurement or reversal of their anticoagulant effect may be indicated. The dilute thrombin time and ecarin-based assays are able to quantify dabigatran across a broad range of concentrations, but are not widely available. A normal thrombin time excludes clinically relevant levels and a normal activated partial thromboplastin time probably excludes excess levels of dabigatran. Factor Xa inhibitors may be quantified with an anti-Xa assay calibrated with drug-specific standards. A normal prothrombin time probably excludes excess levels of rivaroxaban and edoxaban, but not apixaban. Patients with minor and moderate DOAC-associated bleeding can be treated with supportive care and general hemostatic measures. Nonspecific reversal agents (eg, prothrombin complex concentrate, activated prothrombin complex concentrate) are of unproven benefit, carry a risk of thrombosis, and should be reserved for severe bleeding. Specific reversal agents, such as idarucizumab (a monoclonal antibody fragment that binds dabigatran) and andexanet alfa (a recombinant factor Xa variant that binds factor Xa inhibitors but lacks coagulant activity), are in clinical development.
Postpartum hemorrhage: a continuing challenge
Authors: Lockhart Evelyn
Published: September 2016

Obstetric hemorrhage remains a leading cause of maternal morbidity and mortality worldwide. Many postpartum hemorrhages (PPHs) do not have identifiable risk factors; maternity units should therefore have obstetric hemorrhageprotocols in place for all parturients as every pregnancy has the potential to be complicated by hemorrhage. This review will examine the epidemiology of PPH as well as current recommendations for key elements in obstetric hemorrhage protocols. Recent advances in hematologic management of PPH will be also be reviewed, including: (1) recognition of hypofibrinogenemia as a risk factor for severe PPH, (2) use of antifibrinolytic therapy, and (3) strategies for fibrinogen replacement therapy.
Fertility issues in patients with hematologic malignancies
Authors: Loren Alison W.
Published: September 2016

An essential component of a cancer patient's comprehensive care is addressing potential threats to his or her reproductive health. Providers should discuss the risk of infertility with newly diagnosed patients and offer the chance to consult with a reproductive specialist as early as possible. Standard fertility preservation options include embryo or oocyte cryopreservation for women and sperm banking for men; all options for pre-pubertal children are experimental. Patients with hematologic malignancies are a distinct population in whom standard options may present special challenges, and alternative management strategies are being explored. Unique approaches in hematologic malignancy patients include experimental techniques, such as hormonal therapy, referrals to reproductive specialists after cancer treatment, or discontinuation of tyrosine kinase inhibitor therapy in appropriate chronic myelogenous leukemia patients. Importantly, expedited communication between hematologists and reproductive specialists may greatly enhance the quality of care for these patients. Facilitation of referrals will both improve the quality-of-life and expand the prospect of parenthood in survivors. There are ample opportunities to advance the field of oncofertility through additional research, especially in hematologic malignancy patients.
Understanding anemia of chronic disease
Authors: Fraenkel Paula G.
Published: September 2016

The anemia of chronic disease is an old disease concept, but contemporary research in the role of proinflammatory cytokines and iron biology has shed new light on the pathophysiology of the condition. Recent epidemiologic studies have connected the anemia of chronic disease with critical illness, obesity, aging, and kidney failure, as well as with the well-established associations of cancer, chronic infection, and autoimmune disease. Functional iron deficiency, mediated principally by the interaction of interleukin-6, the iron regulatory hormone hepcidin, and the iron exporter ferroportin, is a major contributor to the anemia of chronic disease. Although anemia is associated with adverse outcomes, experimental models suggest that iron sequestration is desirable in the setting of severe infection. Experimental therapeutic approaches targeting interleukin-6 or the ferroportin–hepcidin axis have shown efficacy in reversing anemia in either animal models or human patients, although these agents have not yet been approved for the treatment of the anemia of chronic disease.
Sickle cell trait diagnosis: clinical and social implications
Authors: Naik Rakhi P. , Haywood Carlton
Published: September 2016

The sickle hemoglobin (HbS) point mutation has independently undergone evolutionary selection at least five times in the world because of its overwhelming malarial protective effects in the heterozygous state. In 1949, homozygous Hb S or sickle cell disease (SCD) became the first inherited condition identified at the molecular level; however, since then, both SCD and heterozygous Hb S, sickle cell trait (SCT), have endured a long and complicated history. Hasty adoption of early mass screening programs for SCD, recent implementation of targeted screening mandates for SCT in athletics, and concerns about stigmatization have evoked considerable controversy regarding research and policy decisions for SCT. Although SCT is a largely protective condition in the context of malaria, clinical sequelae, such as exercise-related injury, renal complications, and venous thromboembolism can occur in affected carriers. The historical background of SCD and SCT has provided lessons about how research should be conducted in the modern era to minimize stigmatization, optimize study conclusions, and inform genetic counseling and policy decisions for SCT.
Using red blood cell genomics in transfusion medicine
Authors: Johnsen Jill M.
Published: September 2016

Blood types (blood group antigens) are heritable polymorphic antigenic molecules on the surface of blood cells. These were amongst the first human Mendelian traits identified, and the genetic basis of nearly all of the hundreds of blood types is known. Clinical laboratory methods have proven useful to identify selected blood group gene variants, and use of genetic blood type information is becoming widespread. However, the breadth and complexity of clinically relevant blood group genetic variation poses challenges. With recent advances in next-generation sequencing technologies, a more comprehensive DNA sequence-based genetic blood typing approach is now feasible. This chapter introduces the practitioner to high-resolution genetic blood typing beginning with an overview of the genetics of blood group antigens, the clinical problem of allosensitization, current blood type testing methods, and then discussion of next-generation sequencing and its application to the problem of genetic blood typing.
Treatment of hemophagocytic lymphohistiocytosis in adults
Authors: La Rosée Paul
Published: September 2016

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

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

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

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

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

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

Randomized 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

Despite 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

Stroke 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.
Advances in therapies for non-Hodgkin lymphoma in children
Authors: Kobos Rachel , Terry William
Published: September 2016

Pediatric patients with newly diagnosed, non-Hodgkin Lymphoma (NHL) have an excellent overall survival. However, therapy regimens are associated with acute toxicity and late effects. Furthermore, patients with relapsed or refractory disease have relatively few options with proven clinical benefit. Both histologic and molecular differences exist between adult and pediatric NHL preventing simple translation of adult NHL successes into improvements in pediatric NHL treatment. This review summarizes the introduction of targeted therapies into frontline treatments for patients with anaplastic large-cell lymphoma and CD20–positive tumors, with the goal of improving overall survival while limiting both short- and long-term toxicities. In addition, newer approaches that have limited data in children but may have a significant role in how we treat pediatric NHL in the future are reviewed, which include CD19 directed therapy, Notch inhibition, the tri-functional antibody, FBTA05, and EZH2 inhibition.
Peripheral T-cell lymphoma, NOS, and anaplastic large cell lymphoma
Authors: Beaven Anne W. , Diehl Louis F.
Published: September 2016

Peripheral 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

Langerhans 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.
Treatment of Langerhans cell histiocytosis: role of BRAF/MAPK inhibition
Authors: Abla Oussama , Weitzman Sheila
Published: September 2016

Langerhans cell histiocytosis (LCH) is a clonally derived neoplasm with a highly variable clinical course. Although LCH was once considered a disorder of immune regulation, the identification of activating mutations in the proto-oncogene BRAF-V600E in ∼50%-60% of cases and MEK and ERK phosphorylation in 100% of examined cases, has changed the definition of LCH to a dendritic cell neoplasm with a strong inflammatory component. Current international LCH trials are focused on further improving the outcome of high-risk multisystem LCH patients, by decreasing the reactivation rate, optimizing early salvage regimens, and preventing late sequelae. Anecdotal responses to vemurafenib, a BRAF-V600E inhibitor, have been reported in a few cases of LCH and Erdheim–Chester disease. However, the development of resistance, as well as the potential risks of cutaneous and pancreatic cancers in patients with BRAF-V600E-mutated melanoma treated with single inhibitors, suggest the need for prospective trials with BRAF inhibitors, alone or in combination with other inhibitors of this pathway, for patients with refractory or multiply-relapsed LCH. The recent discovery of somatic mutations in ARAF and in MAP2K1, which lead to activation of the RAS-RAF-MEK –ERK pathway in the setting of wild-type BRAF, as well as the finding that activating mutation in MAP2K1 are relatively insensitive to MEK inhibitors, suggest that a more detailed understanding of this pathway in LCH may be necessary for the development of more effective targeted therapies.
Uncommon histiocytic disorders: Rosai–Dorfman, juvenile xanthogranuloma, and Erdheim–Chester disease
Authors: Haroche Julien , Abla Oussama
Published: September 2016

Rosai–Dorfman disease (RDD), juvenile xanthogranuloma (JXG), and Erdheim–Chester disease (ECD) are non-Langerhans cell (non-LCH) disorders arising from either a dendritic or a macrophage cell. RDD is a benign disorder that presents with massive lymphadenopathy, but can have extranodal involvement. In most cases, RDD is self-limited and observation is the standard approach. Treatment is restricted to patients with life-threatening, multiple-relapsing, or autoimmune-associated disease. JXG is a pediatric histiocytosis characterized by xanthomatous skin lesions that usually resolve spontaneously. In a minority of cases, systemic disease can occur and can be life threatening. Juvenile myelomonocytic leukemia (JMML), as well as germline mutations in NF1 and NF2, have been reported in children with JXG. Recent whole-exome sequencing of JXG cases did not show the BRAF-V600E mutation, although 1 patient had PI3KCD mutation. ECD is an adult histiocytosis characterized by symmetrical long bone involvement, cardiovascular infiltration, a hairy kidney, and retroperitoneal fibrosis. Central nervous system involvement is a poor prognostic factor. Interferon-α is the standard as front-line therapy, although cladribine and anakinra can be effective in a few refractory cases. More than one-half of ECD patients carry the BRAF-V600E mutation. Currently, >40 patients worldwide with multisystemic, refractory BRAF-V600E+ ECD have been treated with vemurafenib, a BRAF inhibitor, which was found to be highly effective. Other recurrent mutations of the MAP kinase and PI3K pathways have been described in ECD. These discoveries may redefine ECD, JXG, and LCH as inflammatory myeloid neoplasms, which may lead to new targeted therapies.
Update in large cell lymphoma: understanding the pathology report
Authors: Hsi Eric D.
Published: September 2016

The 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

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

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

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

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.
RETRACTED ARTICLE: The significance of the change pattern of serum CA125 level for judging prognosis and diagnosing recurrences of epithelial ovarian cancer
Authors: Yang Zhi-jun , Zhao Bing-bing , Li Li
Published: September 2016

Background

Ovarian cancer has the highest mortality rate of the three main malignant tumors of the female reproductive system, with a 5-year overall survival (OS) of only 20–30 %. Approximately 70 % of patients relapse without being cured. To explore the significance of serum CA125 level pre-treatment and the change pattern of CA125 post-treatment for judging prognosis and diagnosing recurrences of epithelial ovarian cancer (EOC).

Methods

A radioimmunoassay was used to continuously monitor levels of serum CA125 in 152 patients with EOC. The first test was done before surgery, then once a month after surgery for more than two consecutive years. The data were analyzed by using Kaplan-Meier curves and the log-rank test, stratified chi-square test, Pearson correlation analysis, and multivariate Cox regression analysis.

Results

(1) There was a relationship between patient outcomes and the serum CA125 levels before treatment and the extent and speed of serum CA125 decrease after treatment. The outcomes of patients with pre-treatment serum CA125 ≤ 35 U/ml were better than those with serum CA125 > 35 U/ml; the outcomes of patients with serum CA125 who had a logarithmic decrease or a decrease to normal within a month after treatment were also better than those with a non-logarithmic decrease or a decrease to normal that took longer than a month. (2) The results of multivariate Cox regression analysis showed that serum CA125 levels before treatment and a decreased speed of decline after treatment were independent prognostic factors; (3) The mean level of serum CA125 at relapse was 116.28 U/ml. The average time from serum CA125 increase to detection of a recurrent lesion by physical or imaging examination was 122 days. The correlation coefficient of serum CA125 level increase and tumor recurrence time was −0.674. (4) The area under the Receiver Operating Characteristic (ROC) curve of serum CA125 for diagnosing EOC recurrence was 0.879, and the sensitivity and specificity were 67.39 and 86.79 %, respectively.

Conclusions

It is important to monitor serum CA125 levels pre-treatment and the change pattern of CA125 post-treatment for judging prognosis and diagnosing recurrences of EOC.
Technical Advance: Changes in neutrophil migration patterns upon contact with platelets in a microfluidic assay
Authors: Frydman Galit H , Le Anna , Ellett Felix , Jorgensen Julianne , Fox James G , Tompkins Ronald G , Irimia Daniel
Published: September 2016

Neutrophils are traditionally regarded as the “first responders” of the immune system. However, recent observations revealed that platelets often respond earlier to recruit and activate neutrophils within sites of injury and inflammation. Currently, platelet–neutrophil interactions are studied by intravital microscopy. Although such studies provide exceptional, physiologic in vivo data, they are also laborious and have low throughput. To accelerate platelet–neutrophil interaction studies, we have developed and optimized an ex vivo microfluidic platform with which the interactions between platelets and moving neutrophils are measured at single-cell level in precise conditions and with high throughput. With the use of this new assay, we have evaluated changes in neutrophil motility upon direct contact with platelets. Motility changes include longer distances traveled, frequent changes in direction, and faster neutrophil velocities compared with a standard motility response to chemoattractant fMLP. We also found that the neutrophil–platelet direct interactions are transient and mediated by CD62P–CD162 interactions, localized predominantly at the uropod of moving neutrophils. This “crawling,” oscillatory neutrophil behavior upon platelet contact is consistent with previous in vivo studies and validates the use of this new test for the exploration of this interactive relationship.