bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk prediction of maternal cardiovascular disease one year after hypertensive pregnancy complications or gestational diabetes mellitus
Authors: Moe Kjartan , Sugulle Meryam , Dechend Ralf , Staff Anne Cathrine
Published: October 2019

Background

Previous preeclampsia, gestational hypertension and gestational diabetes mellitus show a firm epidemiological association to maternal cardiovascular disease risk. Cardiovascular disease risk assessment is recommended in women after these pregnancy complications, but not offered in most countries. We therefore wanted to evaluate the applicability of currently recommended cardiovascular disease risk scores for women one-year postpartum of such pregnancy complications.

Design and methods

We tested applicability of three scoring systems, the Atherosclerotic Cardiovascular Disease (ASCVD) score, the Joint British Societies for the Prevention of Cardiovascular Disease (JBS3) score and Framingham 30 year Risk Score-Cardiovascular Disease (FRS-CVD) in 235 women one-year postpartum (controls: 94, gestational hypertension: 35, preeclampsia: 81, gestational diabetes mellitus: 25). Statistical analysis was performed with Mann–Whitney U test for continuous and Fisher’s mid-corrected p and Pearson’s r for dichotomous variables. A value of p < 0.050 was considered significant.

Results

Most women (87.7%) were below 40 years of age, rendering 10-year risk estimations recommended by American and European societies inapplicable. FRS-CVD could be assessed in all women. Significantly fewer could be assessed by the ASCVD (81.5%) and JBS3 (91.6%). All scoring systems showed small, but significant increases in risk scores for one or more of the pregnancy complication groups, but none at the risk magnitude for cardiovascular disease shown in epidemiological studies.

Conclusion

We demonstrate that ASCVD, JBS3 and FRS-CVD are inadequate in assessing cardiovascular disease risk one-year postpartum. We suggest that pregnancy complications need to be considered separately when evaluating maternal cardiovascular disease risk and need for postpartum follow-up.
Feline coronavirus-associated myocarditis in a domestic longhair cat
Authors: Ernandes Maria A , Cantoni Anna M , Armando Federico , Corradi Attilio , Ressel Lorenzo , Tamborini Alice
Published: October 2019

Case summary

A 9-month-old entire male domestic longhair indoor cat presented with a 3-week history of fluctuating fever, weight loss and small intestine diarrhoea, which was unresponsive to antibiotics and supportive treatment. Abdominal ultrasound revealed severe jejunal and ileocolic junction intestinal wall thickening with loss of layering. An enterectomy was performed and histopathology revealed severe pyogranulomatous enteritis with vasculitits, compatible with the diagnosis of feline infectious peritonitis (FIP). Four days after surgery, the cat re-presented with anorexia and acute onset of expiratory dyspnoea. Echocardiography showed left ventricular hypertrophy and bilateral atrial enlargement. Congestive heart failure caused by hypertrophic cardiomyopathy was suspected and treatment with furosemide was started, which led to amelioration of the clinical signs. The following day, four-limb ataxia, hypermetria and bilateral uveitis were evident. Given the persistent anorexia and worsening of the clinical signs, the cat was humanely euthanized and a post-mortem examination was performed. Necropsy revealed multifocal pyogranulomatous lesions involving multiple organs (adrenal glands, kidneys, lungs, brain, myocardium, lymph nodes, liver), compatible with the diagnosis of FIP. Immunohistochemistry performed on the myocardium revealed feline coronavirus-positive macrophages associated with pyogranulomatous lesions, justifying a diagnosis of feline coronavirus-associated myocarditis.

Relevance and novel information

To the authors’ knowledge, the case described here represents the first published report of feline coronavirus-associated myocarditis. This should be considered as a possible differential diagnosis in cats presenting with cardiac-related signs and other clinical signs compatible with FIP.
The Implications of Paraspinal Muscle Atrophy in Low Back Pain, Thoracolumbar Pathology, and Clinical Outcomes After Spine Surgery: A Review of the Literature
Authors: He Kevin , Head Jeffery , Mouchtouris Nikolaos , Hines Kevin , Shea Phelan , Schmidt Richard , Hoelscher Christian , Stricsek Geoffrey , Harrop James , Sharan Ashwini
Published: October 2019

Study Design:

Literature review.

Objectives:

Paraspinal muscle integrity is believed to play a critical role in low back pain (LBP) and numerous spinal deformity diseases and other pain pathologies. The influence of paraspinal muscle atrophy (PMA) on the clinical and radiographic success of spinal surgery has not been established. We aim to survey the literature in order to evaluate the impact of paraspinal muscle atrophy on low back pain, spine pathologies, and postoperative outcomes of spinal surgery.

Methods:

A review of the literature was conducted using a total of 267 articles identified from a search of the PubMed database and additional resources. A full-text review was conducted of 180 articles, which were assessed based on criteria that included an objective assessment of PMA in addition to measuring its relationship to LBP, thoracolumbar pathology, or surgical outcomes.

Results:

A total of 34 studies were included in this review. The literature on PMA illustrates an association between LBP and both decreased cross-sectional area and increased fatty infiltration of paraspinal musculature. Atrophy of the erector spinae and psoas muscles have been associated with spinal stenosis, isthmic spondylolisthesis, facet arthropathy, degenerative lumbar kyphosis. A number of studies have also demonstrated an association between PMA and worse postoperative outcomes.

Conclusions:

PMA is linked to several spinal pathologies and some studies demonstrate an association with worse postoperative outcomes following spinal surgery. There is a need for further research to establish a relationship between preoperative paraspinal muscle integrity and postoperative success, with the potential for guiding surgical decision making.
Coccidioidomycosis Chorioretinitis
Authors: Nordstrom Brian , Sherpa Namgyal , Marshall Meagan , Chawla Anuj , Heidari Arash , Johnson Royce
Published: October 2019

Coccidioidomycosis is an invasive fungus found primarily in the soil of Southwestern United States, Mexico, and Central America. Primary disease mostly presents as a pulmonary disease although multiple organ systems can be affected through lymphohematogenous dissemination, with ocular seeding extremely rare. When present, the anterior segment structures are most commonly affected. Isolated choroid and/or vitreal disease has been reported infrequently. This is a case of chorioretinitis with vitreal involvement.
Prevalence of MRI Shoulder Abnormalities in Asymptomatic Professional and Collegiate Ice Hockey Athletes
Authors: Hacken Brittney , Onks Cayce , Flemming Donald , Mosher Timothy , Silvis Matthew , Black Kevin , Stuck Dan , Dhawan Aman
Published: October 2019

Background:

The literature demonstrates a high prevalence of asymptomatic knee and hip findings on magnetic resonance imaging (MRI) in athletes. Baseball pitchers are shown to have a high prevalence of asymptomatic shoulder MRI findings, but the incidence of asymptomatic shoulder MRI findings has not been systematically evaluated in nonthrowing contact athletes.

Purpose/Hypothesis:

The purpose of this study was to determine the prevalence of shoulder abnormalities in asymptomatic professional and collegiate hockey players. We hypothesized that, similar to overhead throwing athletes, ice hockey players will have a high prevalence of asymptomatic MRI findings, including labral, acromioclavicular (AC), and rotator cuff pathology on MRI.

Study Design:

Cross-sectional study; Level of evidence, 4.

Methods:

A total of 25 asymptomatic collegiate and professional hockey players (50 shoulders) with no history of missed games or practice because of shoulder injury, pain, or dysfunction underwent bilateral shoulder noncontrast 3.0-T MRI. MRIs were read blinded by 2 board-certified radiologists at 2 separate time points, 3 months apart, to determine the prevalence of abnormalities of the joint fluid, bone marrow, rotator cuff tendon, biceps tendon, labrum, AC joint, and glenohumeral joint. Interrater and intrareader reliability was determined, and regression analysis was performed to identify the prevalence and relationship to stick-hand dominance.

Results:

Labral abnormalities were seen in 25% of the shoulders. AC joint abnormalities and rotator cuff findings were noted in 8% and 6% of shoulders, respectively. One shoulder was noted to have a biceps tendon abnormality, and 1 shoulder demonstrated glenohumeral joint chondral findings. Interrater reliability coefficients were 0.619 for labral abnormalities. Intrareader reliability kappa coefficients were 0.493 and 0.718 for both readers, respectively, for labral abnormalities. Regression analysis was performed and revealed that the overall shoulder pathology was more common in the nondominant stick hand (top stick hand) (coefficient –0.731; P = .021).

Conclusion:

Professional and collegiate ice hockey players had an overall prevalence of labral abnormalities in 25% of their shoulders, with findings more often found in the nondominant stick hand. Rotator cuff abnormalities were uncommon in ice hockey players. These findings differ significantly from published reports examining professional baseball players and other overhead sports athletes.
The Network Structure of Police Misconduct
Authors: Wood George , Roithmayr Daria , Papachristos Andrew V.
Published: October 2019

Conventional explanations of police misconduct generally adopt a microlevel focus on deviant officers or a macrolevel focus on the top-down organization of police departments. Between these levels are social networks of misconduct. This study recreates these networks using data on 16,503 complaints and 15,811 police officers over a six-year period in Chicago. We examine individual-level factors associated with receiving a complaint, the basic properties of these misconduct networks, and factors related to officer co-naming in complaints. We find that the incidence of police misconduct is associated with attributes including race, age, and tenure and that almost half of police officers are connected in misconduct ties in broader networks of misconduct. We also find that certain dyadic factors, especially seniority and race, strongly predict network ties and the incidence of group misconduct. Our results provide actionable information regarding possible ways to leverage the co-complaint network structure to reduce misconduct.
A Case of Gastric Amphicrine Signet-Ring Cell Carcinoma
Authors: Hanamatsu Yuki , Saigo Chiemi , Asano Nami , Kito Yusuke , Nakada Kazuhiko , Takeda Yohei , Takeuchi Tamotsu
Published: October 2019

“Amphicrine” (in Greek, amphi- means “both” or “double”) refers to cells that synchronously exhibit the endocrine and exocrine phenotypes. Gastric amphicrine carcinoma is very rare, and only a few case reports are found in the English literature; thus, its pathobiological features remain unclear. Here, we report a case of amphicrine gastric carcinoma. A woman in her sixth decade of life presented with anemia and underwent upper endoscopy, followed by histopathological examination of biopsy specimens. She appeared to have gastric cancer with a tumor measuring 5.0 cm × 4.0 cm in size. Subsequently, the patient underwent total gastrectomy with lymph node dissection. Histopathological examination revealed a poorly cohesive carcinoma that sparsely coexisted with signet-ring cell carcinoma cells with regional lymph node metastasis. Interestingly, synaptophysin immunoreactivity with the coexistence of Alcian blue was found in individual signet-ring cell carcinoma cells. Furthermore, the present amphicrine carcinoma cells immunohistochemically expressed CD44 variant 9, a functional cancer stem cell marker. We believe that the present case findings may support the idea of multipotent stem cells being an origin of amphicrine gastric cancers.
Atypical Vasa Previa in a Velamentous Cord Insertion Identified During Sonographic Examination
Authors: Gandhi Amanda
Published: October 2019

Vasa previa is a life-threatening complication of a velamentous cord insertion. Understanding variations of this condition is vital to ensuring optimal patient outcomes. The case presented is of a 27-year-old primigravida woman whose condition was diagnosed during her second-trimester obstetric sonographic examination. The case demonstrated an unusual variation of vasa previa, in which a single fetal vessel separated from the membranous insertion located near the fundal placenta and traversed posteriorly through the chorionic membrane to within 0.83 cm of the internal os. The case was followed with the most up-to-date standards recommended by the American Institute of Ultrasound in Medicine.
New Insights into the Pathophysiology of Acquired Cytopenias
Authors: Young Neal S. , Abkowitz Janis L. , Luzzatto Lucio
Published: October 2019

This review addresses three related bone marrow failure diseases, the study of which has generated important insights in hematopoiesis, red cell biology, and immune-mediated blood cell injury. In Section I, Dr. Young summarizes the current knowledge of acquired aplastic anemia. In most patients, an autoimmune mechanism has been inferred from positive responses to nontransplant therapies and laboratory data. Cytotoxic T cell attack, with production of type I cytokines, leads to hematopoietic stem cell destruction and ultimately pancytopenia; this underlying mechanism is similar to other human disorders of lymphocyte-mediated, tissue-specific organ destruction (diabetes, multiple sclerosis, uveitis, colitis, etc.). The antigen that incites disease is unknown in aplastic anemia as in other autoimmune diseases; post-hepatitis aplasia is an obvious target for virus discovery. Aplastic anemia can be effectively treated by either stem cell transplantation or immunosuppression. Results of recent trials with antilymphocyte globulins and high dose cyclophosphamide are reviewed.

Dr. Abkowitz discusses the diagnosis and clinical approach to patients with acquired pure red cell aplasia, both secondary and idiopathic, in Section II. The pathophysiology of various PRCA syndromes including immunologic inhibition of red cell differentiation, viral infection (especially human parvovirus B19), and myelodysplasia are discussed. An animal model of PRCA (secondary to infection with feline leukemia virus [FeLV], subgroup C) is presented. Understanding the mechanisms by which erythropoiesis is impaired provides for insights into the process of normal red cell differentiation, as well as a rational strategy for patient management.

Among the acquired cytopenias paroxysmal nocturnal hemoglobinuria (PNH) is relatively rare; however, it can pose formidable management problems. Since its first recognition as a disease, PNH has been correctly classified as a hemolytic anemia; however, the frequent co-existence of other cytopenias has hinted strongly at a more complex pathogenesis. In Section III, Dr. Luzzatto examines recent progress in this area, with special emphasis on the somatic mutations in the PIG-A gene and resulting phenotypes. Animal models of PNH and the association of PNH with bone marrow failure are also reviewed. Expansion of PNH clones must reflect somatic cell selection, probably as part of an autoimmune process. Outstanding issues in treatment are illustrated through clinical cases of PNH. Biologic inferences from PNH may be relevant to our understanding of more common marrow failure syndromes like myelodysplasia.
Platelets: New Understanding of Platelet Glycoproteins and Their Role in Disease
Authors: Bussel James B. , Kunicki Thomas J. , Michelson Alan D.
Published: October 2019

This review covers new developments and their clinical implications in three areas: platelet antigen polymorphisms, inhibition of platelet glycoprotein IIb-IIIa, and autoimmune thrombocytopenia (ITP).

In Section I, Dr. Kunicki reviews platelet polymorphisms and their clinical implications. A current tabulation of the numerous platelet antigens, both those that are platelet specific and not platelet specific, are summarized. The immunogenic clinical implications of these polymorphisms are considered, including fetal and neonatal alloimmune thrombocytopenia, post transfusion purpura, and refractoriness to platelet transfusion. The functional relationship to hemostasis and thrombosis is also discussed, in particular whether one haplotype of the PIA1/PIA2 (HPA-1a/1b) polymorphism predisposes to myocardial infarction. Finally, novel investigations of polymorphisms will be considered, including hormonal induction of certain polymorphisms.

In Section II, Dr. Michelson reviews the newest generation of platelet inhibitors, those blocking glycoprotein IIB/IIIA, from the point of view of the hematologist who might be consulted about a patient receiving this form of treatment. The current use of available IIb-IIIa inhibitors and those in trial and the accepted and possible future indications for their use are addressed. The mechanism of action and actual and theoretical advantages and disadvantages of each inhibitor are explored. Scenarios that prompt consultation with a hematologist are presented, including management of bleeding, thrombocytopenia, and management of the patient requiring emergency surgery.

In Section III, Dr. Bussel reviews controversies in ITP, looking at both the current state of the art and the potential for the future. Case presentations are used to illustrate the issues in both children and adults. Three primary areas are addressed: 1) the diagnosis of ITP, 2) when and for which patient to recommend splenectomy, and 3) the management of the refractory splenectomized patient who still has a low platelet count and bleeding symptoms.
Hematopoietic Cell Transplantation for Benign Hematological Disorders and Solid Tumors
Authors: Storb Rainer F. , Lucarelli Guido , McSweeney Peter A. , Childs Richard W.
Published: October 2019

Allogeneic hematopoietic cell transplantation (HCT) has been successfully used as replacement therapy for patients with aplastic anemia and hemoglobinopathies. Both autologous and allogeneic HCT following high-dose chemotherapy can correct manifestations of autoimmune diseases. The impressive allogeneic graft-versus-tumor effects seen in patients given HCT for hematological malignancies have stimulated trials of allogeneic immunotherapy in patients with otherwise refractory metastatic solid tumors. This session will update the status of HCT in the treatment of benign hematological diseases and solid tumors.

In Section I, Dr. Rainer Storb reviews the development of nonmyeloablative conditioning for patients with severe aplastic anemia who have HLA-matched family members. He also describes the results in patients with aplastic anemia given HCT from unrelated donors after failure of responding to immunosuppressive therapy. The importance of leuko-poor and in vitro irradiated blood product transfusions for avoiding graft rejection will be discussed.

In Section II, Dr. Guido Lucarelli reviews the status of marrow transplantation for thalassemia major and updates results obtained in children with class I and class II severity of thalassemia. He also describes results of new protocols for class III patients and efforts to extend HCT to thalassemic patients without HLA-matched family members.

In Section III, Dr. Peter McSweeney reviews the current status of HCT for severe autoimmune diseases. He summarizes the results of autologous HCT for systemic sclerosis, multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus, and reviews the status of planned Phase III studies for autologous HCT for these diseases in North America and Europe. He also discusses a possible role of allogeneic HCT in the treatment of these diseases.

In Section IV, Dr. Richard Childs discusses the development and application of nonmyeloablative HCT as allogeneic immunotherapy for treatment-refractory solid tumors. He reviews the results of pilot clinical trials demonstrating graft-versus-solid tumor effects in a variety of metastatic cancers and describes efforts to characterize the immune cell populations mediating these effects, as well as newer methods to target the donor immune system to the tumor.
Venous Thrombosis: The Role of Genes, Environment, and Behavior
Authors: Rosendaal Frits R.
Published: October 2019

Over the last decade we have witnessed an avalanche of newly identified risk factors for venous thrombosis. This has advanced our knowledge of its etiology, because more determinants have been described and because the underlying concepts have received a new and broader understanding.

Venous thrombosis is a common multicausal disease occurring as the result of interacting genetic, environmental and behavioral risk factors. Some of these have been known since medieval times, such as the increased risk of thrombosis during immobilization in pregnancy and after childbirth (although retained milk of the breast-feeding mother was seen as the primary cause for the latter). Pregnancy and puerperium still cause thrombosis, as do exogenous hormones in oral contraceptives and hormonal replacement therapy. Furthermore, the immobilization in the puerperium of the old days translates directly to situations of immobilization in current times, such as prolonged travel in airplanes or excessive electronic gaming.

While pedigrees with abundant thrombosis were observed in the early 1900s, the first cause of heritable thrombophilia (antithrombin deficiency) was discovered in 1965, with the subsequent identification of deficiencies of protein C and protein S in the early 1980s. These were uncommon and strong risk factors, whereas the more recently discovered genetic variants are common and weak, and cause disease only in the presence of other factors.
Targeting the IAP Family of Caspase Inhibitors as an Emerging Therapeutic Strategy
Authors: Schimmer Aaron D. , Dalili Shadi
Published: October 2019

The IAPs (inhibitor of apoptosis proteins) are a family of caspase inhibitors that block the execution phase of apoptosis. Overexpression of IAPs confers chemoresistance and, in some groups of patients, is associated with a poor prognosis. Given their role in the development and progression of solid tumors and hematologic malignancies, efforts are underway to develop therapeutic IAP inhibitors, with a focus on X-linked IAP (XIAP) and survivin. Antisense oligonucleotides that target XIAP and survivin have been developed and are currently in phase I clinical trial. Small-molecules that bind and inhibit XIAP have also been identified and are in the process of clinical development. This review focuses on the preclinical data that support the development of IAP-targeted therapies.
Diagnosis and Treatment of Childhood Non-Hodgkin Lymphoma
Authors: Reiter Alfred
Published: October 2019

Major advances have been made in the treatment of childhood non-Hodgkin lymphoma (NHL). The recognition that different NHL subtypes require different treatment strategies was fundamental to developing successful therapy regimens. Currently established therapy groups are lymphoblastic lymphoma (LBL) of precursor B- or T-cell type, mature B-cell neoplasms (B-NHL), and anaplastic large cell lymphoma (ALCL). Accurate diagnostic classification is crucial for allocating patients to appropriate treatment groups. Therapy protocols designed to treat children with acute lymphoblastic leukemia (ALL) have proven highly efficacious for treating children with LBL and are associated with event-free survival (EFS) rates up to 80%. For children with B-NHL, a strategy of rapidly repeated short, dose-intense courses proved more efficacious, with EFS rates up to 90%. In patients with ALCL, comparable results are achieved with either strategy, although this group has the highest relapse rate. The price of these efficacious treatments is considerable toxicity. On the other hand, the chance to survive after relapse is still dismal due to the almost complete lack of established salvage regimen. Thus, refinement of the balance between treatment burden and individual patient risk for failure is a major future task. A variety of new treatment options, some already established for treating adult NHL, await evaluation in childhood NHL.
Monitoring disease response in chronic-phase chronic myeloid leukemia: the age of molecular assays?
Authors: Yeung David T. , Branford Susan
Published: October 2019

An 80-year-old man has newly diagnosed chronic myeloid leukemia. His BM and blood examination at diagnosis confirms chronic-phase disease, with the Philadelphia chromosome as the sole cytogenetic abnormality. He has intermediate Sokal and Hasford risk,1 and is started on imatinib 600 mg once daily. He lives 5 hours away from the nearest specialist hematology service and prefers followup with his local physician, who cannot perform BM examinations. In patients such as this, is it acceptable to monitor his therapeutic response solely with molecular studies of his peripheral blood?
Gaucher disease and other storage disorders
Authors: Grabowski Gregory A.
Published: October 2019

In 1882, Philippe Gaucher described a 32-year-old woman with massive splenomegaly and unusually large cells in the spleen, which he called a “primary epithelioma of the spleen.” The systemic nature and inheritance of the disease and its variants involving the viscera and CNS were described over the next century. The delineation of the causal enzymatic defects, genetics, molecular pathology, and genomics have provided pathogenic insights into the phenotypic spectrum and the bases for development of specific therapies for what is now known as Gaucher disease. As a prototype, the clinically and economically successful intracellular enzyme therapy provided the impetus for the expansion of similar research and therapeutic developments for other lysosomal storage diseases (LSDs) and orphan diseases, including Fabry, Pompe, and Niemann-Pick diseases, as well as several mucopolysaccharidoses. Continuing studies of such LSDs, which occur as a group in more than 7000 live births, have revealed the complex molecular interdigitation with the autophagy and apoptotic pathways and proteostasis and the impact of disruptions of the lysosomal/autophagy and proteostasis systems on more common diseases has been recognized. Examples include age-related neurodegenerative diseases (eg, Parkinson disease and Gaucher disease), idiopathic hypertrophic myocardiopathies, stroke and renal failure (eg, Fabry disease), and Nonalcoholic Fatty Liver Disease/Nonalcoholic SteatoHepatitis (NAFLD/NASH) and atherosclerosis (eg, lysosomal acid lipase deficiencies). Although perceived as rare, the availability of treatment and the impact of the LSDs on more common diseases require their integration into routine clinical practice.
Novel cellular therapies for leukemia: CAR-modified T cells targeted to the CD19 antigen
Authors: Brentjens Renier J. , Curran Kevin J.
Published: October 2019

The ability of immune-competent donor T cells to mediate a beneficial graft-versus-leukemia (GVL) effect was first identified in the setting of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for hematologic malignancies. Unfortunately, with the exception of chronic myelogenous leukemia and EBV-induced lymphoproliferative disease, allo-HSCT GVL lacks the potency to significantly affect disease progression or recurrence in most other hematologic malignancies. The inadequacy of a GVL effect using past approaches is particularly evident in patients with lymphoid malignancies. However, with the advent of improved gene transfer technology, genetically modified tumor-specific immune effectors have extended cellular immunotherapy to lymphoid malignancies. One promising strategy entails the introduction of genes encoding artificial receptors called chimeric antigen receptors (CARs), which redirect the specificity and function of immune effectors. CAR-modified T cells targeted to the B cell–specific CD19 antigen have demonstrated promising results in multiple early clinical trials, supporting further investigation in patients with B-cell cancers. However, disparities in clinical trial design and CAR structure have complicated the discovery of the optimal application of this technology. Recent preclinical studies support additional genetic modifications of CAR-modified T cells to achieve optimal clinical efficacy using this novel adoptive cellular therapy.
Measuring bleeding as an outcome in clinical trials of prophylactic platelet transfusions
Authors: Bercovitz Rachel S. , O'Brien Sarah H.
Published: October 2019

A 12-year-old girl with acute myeloid leukemia has completed her third cycle of chemotherapy and is in the hospital awaiting count recovery. Her platelet count today is 15 000 and, based on your institution's protocol, she should receive a prophylactic platelet transfusion. She has a history of allergic reactions to platelet transfusions and currently has no bleeding symptoms. The patient's mother questions the necessity of today's transfusion and asks what her daughter's risk of bleeding would be if the count is allowed to decrease lower before transfusing. You perform a literature search regarding the risk of bleeding with differing regimens for prophylactic platelet transfusions.
Hemostatic defects in liver and renal dysfunction
Authors: Mannucci Pier Mannuccio , Tripodi Armando
Published: October 2019

Multiple and complex abnormalities of hemostasis are revealed by laboratory tests in such common diseases as cirrhosis and end-stage renal insufficiency. Because these abnormalities are associated with a bleeding tendency, a causal relationship is plausible. Accordingly, an array of transfusional and nontransfusional medications that improve or correct these abnormalities is used to prevent or stop hemorrhage. However, recent data indicate that the use of hemostatic drugs is scarcely justified mechanistically or clinically. In patients with uremia, the bleeding tendency (mainly expressed by gastrointestinal bleeding and hematoma formation at kidney biopsy) is reduced dramatically by the improvement of anemia obtained with the regular use of erythropoietin. In cirrhosis, the most severe and frequent hemorrhagic symptom (acute bleeding from esophageal varices) is not explained by abnormalities in such coagulation screening tests as the prothrombin and partial thromboplastin times, because formation of thrombin the final coagulation enzyme is rebalanced by low naturally occurring anticoagulant factors in plasma that compensate for the concomitant decrease of procoagulants. Rebalance also occurs for hyperfibrinolysis and platelet abnormalities. These findings are consistent with clinical observations that transfusional and nontransfusional hemostatic medications are of little value as adjuvants to control bleeding in advanced liver disease. Particularly in uremia, but also in cirrhosis, thrombosis is becoming a cogent problem.
Umbilical cord blood transplantation: a maturing technology
Authors: Oran Betul , Shpall Elizabeth
Published: October 2019

The use of umbilical cord blood (CB) as a source of hematopoietic progenitor cells for patients with high-risk hematologic disorders receiving allogeneic hematopoietic cell transplantations (HCTs) has increased significantly. Single-institution and registry studies have shown a decreased relapse rate and an increased transplantation-related mortality rate with similar overall survival rates after allogeneic HCT with CB compared with other donor sources. The transplantation of double CB units has overcome the dose limitation inherent in a single CB unit and thus has markedly extended the use of CB to larger children and adults. Similarly, the use of reduced intensity conditioning in the CB transplantation setting has allowed the treatment of older patients who would be unable to tolerate the myeloablative regimens used in the original CB transplantation protocols.
Emerging ‘A’ therapies in hemoglobinopathies: agonists, antagonists, antioxidants, and arginine
Authors: Vichinsky Elliott
Published: October 2019

Sickle cell disease and thalassemia have distinctly different mutations, but both share common complications from a chronic vasculopathy. In the past, fetal hemoglobin–modulating drugs have been the main focus of new therapy, but the increased understanding of the complex pathophysiology of these diseases has led to the development of novel agents targeting multiple pathways that cause vascular injury. This review explores the pathophysiology of hemoglobinopathies and novel drugs that have reached phase 1 and 2 clinical trials. Therapies that alter cellular adhesion to endothelium, inflammation, nitric oxide dysregulation, oxidative injury, altered iron metabolism, and hematopoiesis will be highlighted. To evaluate these therapies optimally, recommendations for improving clinical trial design in hemoglobinopathies are discussed.
Advances in stem cell transplantation and gene therapy in the β-hemoglobinopathies
Authors: Payen Emmanuel , Leboulch Philippe
Published: October 2019

High-level production of β-globin, γ-globin, or therapeutic mutant globins in the RBC lineage by hematopoietic stem cell gene therapy ameliorates or cures the hemoglobinopathies sickle cell disease and beta thalassemia, which are major causes of morbidity and mortality worldwide. Considerable efforts have been made in the last 2 decades in devising suitable gene-transfer vectors and protocols to achieve this goal. Five years ago, the first βE/β0-thalassemia major (transfusion-dependent) patient was treated by globin lentiviral gene therapy without injection of backup cells. This patient has become completely transfusion independent for the past 4 years and has global amelioration of the thalassemic phenotype. Partial clonal dominance for an intragenic site (HMGA2) of chromosomal integration of the vector was observed in this patient without a loss of hematopoietic homeostasis. Other patients are now receiving transplantations while researchers are carefully weighing the benefit/risk ratio and continuing the development of further modified vectors and protocols to improve outcomes further with respect to safety and efficacy.
Aplastic anemia: therapeutic updates in immunosuppression and transplantation
Authors: Scheinberg Phillip
Published: October 2019

Advances in hematopoietic stem cell transplantation (HSCT) and immunosuppressive therapy (IST) have improved survival in severe aplastic anemia (SAA) from 10%-20% in the 1960s to 80%-90% today. A matched sibling HSCT is the treatment of choice in younger patients, whereas IST is often used in older patients or in those who lack a histocompatible sibling. Graft rejection, GVHD, and poor immune reconstitution (with associated infectious complications) limit the success of HSCT, whereas lack of response, relapse, and clonal evolution limit the success of IST. The historically high rate of graft rejection in SAA is now less problematic in the matched setting, but with greater rates observed with unrelated and umbilical cord donors. The correlation of increasing age with the risk of GVHD and the significant morbidity and mortality of this transplantation complication continue to affect the decision to pursue HSCT versus IST as initial therapy in adults with SAA. Outcomes with matched unrelated donor HSCT have improved, likely due to better donor selection, supportive care, and improved transplantation protocols. Results with mismatched unrelated donor and umbilical HSCT are not as favorable, with higher rates of graft rejection, GVHD, and infectious complications. Investigation of several upfront alternative IST protocols has not improved outcomes beyond horse antithymocyte globulin and cyclosporine. More recently, the role of alemtuzumab in SAA has been better defined and an oral thrombomimetic, eltrombopag, is showing promising activity in refractory cases. The most recent advances in HSCT and IST in SAA are discussed in this review.
The conundrum of neonatal coagulopathy
Authors: Revel-Vilk Shoshana
Published: October 2019

The maturation and postnatal development of the human coagulation system was first studied and described more than 20 years ago. These older studies, supported by more recent data, confirm the significant and important differences in the physiology of coagulation and fibrinolysis in neonates and young children compared with older children and adults. Subsequently, significant differences were also described in the physiology of primary hemostasis and in global in vitro tests for hemostasis. These differences, which mostly reflect the immaturity of the neonatal hemostasis system, are functionally balanced. Healthy neonates show no signs of easy bruising or other bleeding diathesis and no increased tendency to thrombosis for any given stimulus compared with adults. Systemic diseases may affect hemostasis, predisposing ill neonates to increased hemorrhagic or thrombotic complications. The immaturity of the hemostasis system in preterm and very-low-birth-weight neonates may contribute to a higher risk for intraventricular hemorrhage. Therapies targeting the hemostasis system can be effective for preventing and treating these events. The concept of “neonatal coagulopathy” has an important impact on both the diagnosis and management of hemorrhagic or thrombotic events in neonates. For diagnosis of hemostasis disorders, diagnostic laboratories processing pediatric samples should use age-, analyzer-, and reagent-appropriate reference ranges. Age-specific guidelines should be followed for the management of neonates with hemostatic disorders.
Myelodysplastic syndromes: who and when in the course of disease to transplant
Authors: Mufti Ghulam J. , Potter Victoria
Published: October 2019

The myelodysplastic syndromes are clonal hematopoietic disorders for which hematopoietic stem cell transplantation remains the only curative therapy. The timing of transplantation, methods of disease risk stratification, patient selection, pretransplantation therapies, and preparative regimens have evolved over the years, resulting in increasing disease-free survival. In recent years, alternative donor sources have been demonstrated to be a viable alternative to traditional sibling and matched unrelated donor stem cell sources. Efforts at transplantation regimen development continue with the aim of maximizing the chances of cure with minimal toxicity and improved quality of life. Integrating new knowledge regarding disease biology will be critical to continue to improve the success of hematopoietic stem cell transplantation. Exciting areas of ongoing research that may lead to reductions in posttransplantation relapse rate include posttransplantation therapies such as DNA methyltransferase inhibitors, vaccine strategies, and donor lymphocyte infusions to enhance the GVL effect.
Thrombotic disease in the myeloproliferative neoplasms
Authors: Falanga Anna , Marchetti Marina
Published: October 2019

Thrombosis is a leading cause of morbidity and mortality in patients with Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs), particularly polycythemia vera and essential thrombocythemia. Mechanisms involved in the pathogenesis of the acquired thrombophilic state associated with these diseases include abnormalities of MPN clone–derived blood cells, which display prothrombotic features, and abnormalities of normal vascular cells, which become procoagulant in response to inflammatory stimuli. Ultimately, the release into the blood of elevated levels of procoagulant microparticles by platelets and vascular cells and the increase in the global thrombin generation due to an acquired activated protein C resistance result in a highly prothrombotic scenario in patients with polycythemia vera and essential thrombocythemia. The acquired point mutation in the pseudokinase domain of JAK2 (JAK2V617F) in these disorders is variably associated with thrombosis and, more consistently, with elevations in WBC counts and alterations in biomarkers of blood-clotting abnormalities. The predictive value of these biomarkers for thrombosis remains to be established to identify subsets of patients at elevated risk who may benefit from prophylaxis with antithrombotic drugs.
Large granular lymphocytic leukemia: molecular pathogenesis, clinical manifestations, and treatment
Authors: Zhang Dan , Loughran Thomas P.
Published: October 2019

Large granular lymphocyte (LGL) leukemia represents a spectrum of rare lymphoproliferative diseases defined by clonal amplification of either CD3+ cytotoxic T-lymphocytes or CD3− natural killer cells. This chapter focuses on the T-cell form of LGL leukemia. Clinical features include neutropenia, anemia, and rheumatoid arthritis. LGL leukemia is thought to arise from chronic antigenic stimulation, with the long-term survival of LGL being promoted by constitutive activation of multiple survival signaling pathways, such as the JAK/STAT3, sphingolipid, and Ras/MEK/ERK pathways. Therefore, these lead to global deregulation of apoptosis and resistance to normal pathways of activation-induced cell death. The majority of LGL leukemia patients eventually need treatment. Treatment of leukemic LGL is based on immunosuppressive therapy, primarily using low doses of methotrexate or cyclophosphamide. However, no standard therapy has been established because of the lack of large, prospective trials. In addition, because some patients are refractory to currently available treatments and none of these therapeutic modalities can cure LGL leukemia, new therapeutic options are needed. Understanding the current state of the pathogenesis of LGL leukemia may provide insights into novel therapeutic options.
Plasma exchange: concepts, mechanisms, and an overview of the American Society for Apheresis guidelines
Authors: Winters Jeffrey L.
Published: October 2019

Plasma exchange is a therapeutic procedure used to treat a variety of diseases through the bulk removal of plasma. To apply this treatment to patients appropriately, it is essential to understand the methods to remove plasma, its effects on normal plasma constituents, the role of replacement fluids in the treatment, and the risks associated with the procedure. To facilitate the appropriate evidence-based use of plasma exchange and to encourage research, the American Society for Apheresis has published guidelines providing practical guidance and information to those responsible for ordering or providing this treatment.
A look into the future: can minimal residual disease guide therapy and predict prognosis in chronic lymphocytic leukemia?
Authors: Ghia Paolo
Published: October 2019

Over the past 2 decades, dramatic improvements in the efficacy of treatments for chronic lymphocytic leukemia have led to progressively higher percentages of clinical complete remissions. A molecular eradication of the leukemia has become not only a desirable, but also an achievable, end point that needs to be evaluated within clinical trials. The assessment of complete remission only at the clinical and morphological level is insufficient, at least for physically fit patients. The detection of minimal residual disease (MRD) in chronic lymphocytic leukemia has become feasible using PCR-based or flow cytometric techniques that reproducibly allow reaching the detection level of less than 1 leukemic cell per 10 000 leukocytes (10−4), the level currently defined as MRD− status. Emerging data indicate that the MRD status during and at the end of treatment is one of the most powerful predictors of progression-free and overall survival. This predictor appears to be independent of clinical response, type or line of therapy, and known biological markers. For these reasons, the time is ripe to test the use of MRD as a surrogate marker of clinical end points and as a real-time marker of efficacy and/or resistance to the administered therapies. In the near future, clinical trials will determine whether MRD assessment can be used for guiding therapy, either to improve quality of responses through consolidation or to prevent relapses through preemptive therapies based on the reappearance of MRD.
Strategies for induction, autologous hematopoietic stem cell transplantation, consolidation, and maintenance for transplantation-eligible multiple myeloma patients
Authors: McCarthy Philip L. , Hahn Theresa
Published: October 2019

There have been major advances in the past decade in the continuum of therapy for transplantation-eligible multiple myeloma patients. For patients requiring therapy, recommended induction treatment consists of triple drug regimens followed by the collection of hematopoietic stem cells. The question of early versus delayed transplantation is under investigation and may identify patients for whom early transplantation is optimal therapy and those for whom it may be delayed. For transplantation-eligible patients, high-dose melphalan remains the standard regimen. After transplantation, consolidation can be considered for patients with less than a complete remission. Maintenance therapy with bortezomib or lenalidomide (or both in very-high-risk patients) is a reasonable option for long-term disease control and improvement in overall survival. Incorporation of new agents into the continuum of multiple myeloma care should result in improved outcomes and long-term disease control.
Hodgkin lymphoma in children and adolescents: improving the therapeutic index
Authors: Kelly Kara M.
Published: October 2019

Hodgkin lymphoma (HL) is a highly curable form of childhood cancer, with estimated 5 year survival rates exceeding 98%. However, the establishment of a “standard of care” approach to its management is complicated by the recognition that long-term overall survival declines in part from delayed effects of therapy and that there continue to be subgroups of patients at risk for relapse for which prognostic criteria cannot adequately define. This challenge has resulted in the development of various strategies aimed at identifying the optimal balance between maintaining overall survival and avoidance of long-term morbidity of therapy, often representing strategies quite different from those used for adults with HL. More precise risk stratification and methods for assessing the chemosensitivity of HL through imaging studies and biomarkers are in evolution. Recent advances in the understanding of the biology of HL have led to the introduction of targeted therapies in both the frontline and relapsed settings. However, significant barriers exist in the development of new combination therapies, necessitating collaborative studies across pediatric HL research consortia and in conjunction with adult groups for the adolescent and young adult (AYA) population with HL.
Role of stem cell transplant and maintenance therapy in plasma cell disorders
Authors: McCarthy Philip L. , Holstein Sarah A.
Published: October 2019

Autologous stem cell transplant (ASCT) has been an important component of therapy for myeloma patients eligible for high-dose chemotherapy. Recent studies comparing early transplant to low-dose chemotherapy support the continued use of ASCT as consolidation following induction therapy, even in the era of immunomodulatory drugs, proteasome inhibitors, and other novel agents. Despite the marked improvements in outcomes with this approach, most patients will eventually experience disease progression. Thus, inclusion of post-ASCT consolidation/maintenance strategies is used to improve long-term disease control. Multiple randomized studies support the use of lenalidomide maintenance therapy following ASCT. The next generation of clinical trials will incorporate novel agents such as monoclonal antibodies, proteasome inhibitors, and other novel pathway modulatory agents into post-ASCT treatment strategies with the goal of achieving even deeper responses and longer durations of disease control.