bluuebunny/crossref_metadata_2025_split huggingface dataset:
New insights in the biology of Hodgkin lymphoma
Authors: Küppers Ralf 
Published: October 2019

AbstractThe Hodgkin and Reed/Sternberg (HRS) tumor cells of classical Hodgkin lymphoma (HL) and the lymphocyte-predominant tumor cells of nodular lymphocyte–predominant HL are both derived from germinal center B cells. HRS cells, however, have largely lost their B-cell gene-expression program and coexpress genes typical of various types of hematopoietic cells. Multiple signaling pathways show a deregulated activity in HRS cells. The genetic lesions involved in the pathogenesis of HL are only partly known, but numerous members and regulators of the NF-κB and JAK/STAT signaling pathways are affected, suggesting an important role for these pathways in HL pathogenesis. Some genetic lesions involve epigenetic regulators, and there is emerging evidence that HRS cells have undergone extensive epigenetic alterations compared with normal B cells. HRS and lymphocyte-predominant cells are usually rare in the lymphoma tissue, and interactions with other cells in the microenvironment are likely critical for HL pathophysiology. T cells represent a main population of infiltrating cells, and it appears that HRS cells both inhibit cytotoxic T cells efficiently and also receive survival signals from Th cells in direct contact with them.
How to use new biology to guide therapy in multiple myeloma
Authors: Morgan Gareth J. , Kaiser Martin F. 
Published: October 2019

Abstract
Recent advances in multiple myeloma (MM) therapy have led to significantly longer median survival rates and some patients being cured. At the same time, our understanding of MM biology and the molecular mechanisms driving the disease is constantly improving. Next-generation sequencing technologies now allow insights into the genetic aberrations in MM at a genome-wide scale and across different developmental stages in the course of an individual tumor. This improved knowledge about MM biology needs to be rapidly translated and transformed into diagnostic and therapeutic applications to finally achieve cure in a larger proportion of patients. As a part of these translational efforts, novel drugs that inhibit oncogenic proteins overexpressed in defined molecular subgroups of the disease, such as FGFR3 and MMSET in t(4;14) MM, are currently being developed. The potential of targeted next-generation diagnostic tests to rapidly identify clinically relevant molecular subgroups is being evaluated. The technical tools to detect and define tumor subclones may potentially become clinically relevant because intraclonal tumor heterogeneity has become apparent in many cancers. The emergence of different MM subclones under the selective pressure of treatment is important in MM, especially in the context of maintenance therapy and treatment for asymptomatic stages of the disease. Finally, novel diagnostic and therapeutic achievements have to be implemented into innovative clinical trial strategies with smaller trials for molecularly defined high-risk patients and large trials with a long follow-up for the patients most profiting from the current treatment protocols. These combined approaches will hopefully transform the current one-for-all care into a more tailored, individual therapeutic strategy for MM patients.
New challenges in hemophilia: long-term outcomes and complications
Authors: Young Guy 
Published: October 2019

AbstractFor the past 5 decades, the care for hemophilia patients has improved significantly to the point that a newborn with hemophilia living in a developed nation can expect to have a normal lifespan and a high quality of life. Despite this, there are several new challenges that the hemophilia community will face in the coming years. First, the hemophilia community will soon be challenged with adopting a variety of new agents into clinical practice. Second, the normalization of patients' lives as a result of improved treatment has led to new problem areas, including obese/overweight hemophiliacs and osteoporosis. In addition, although mortality rates are similar to those of the healthy population, morbidities such as hemophilic arthropathy still occur. Third, the cost of care continues to rise, both due to the development of expensive new therapies and to the costs of managing problems such as obesity and osteoporosis. Finally, most patients in the world with hemophilia receive little to no care and although this is an enormous challenge, it must be confronted. This review discusses some new challenges facing developing nations and their care for hemophilia patients. In summary, in hemophilia in the coming few years, several new challenges will need to be confronted.
Paramount prognostic factors that guide therapeutic strategies in diffuse large B-cell lymphoma
Authors: Sehn Laurie H. 
Published: October 2019

Abstract
Outcome in diffuse large B-cell lymphoma (DLBCL) has improved over the last decade and will likely improve further with the introduction of novel agents. At the present time, clinical prognostic factors are limited in their ability to identify patients with sufficiently poor outcome to justify deviation of therapy away from R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) outside of a clinical trial. Similarly, with the exception of the concurrent translocation of MYC and BCL2, there are no validated biologic markers that can be used to guide initial therapy in routine practice. Recognition of the molecular heterogeneity of DLBCL is of paramount importance and must be taken into consideration when investigating new therapies. It will be vital for novel targeted agents to be evaluated in patient populations enriched for those who are most likely to benefit. The identification of prognostic and predictive biomarkers should be initiated during the early phase of drug development so that these tests can be validated within phase 3 trials. Although currently available techniques such as immunohistochemistry may still be used, gene-expression profiling and whole genomic analytic techniques will likely play a major role in the evaluation of patients in the future to determine optimal personalized treatment for DLBCL.
The many faces of marginal zone lymphoma
Authors: Zinzani Pier Luigi 
Published: October 2019

AbstractIndolent B-cell lymphomas that are supposed to derive from the marginal zone (marginal zone lymphomas [MZLs]) include 3 specific entities: extranodal marginal zone lymphoma (EMZL) or mucosa-associated lymphatic tissue (MALT) lymphoma, splenic MZL (SMZL), and nodal MZL (NMZL). The clinical and molecular characteristics are different for each entity, with some shared phenotypic and genetic features. EMZL is the most common entity, accounting for approximately 70% of all MZLs. These neoplasms can arise at virtually any extranodal site and are commonly associated with chronic antigenic stimulation either as a result of infection (eg, Helicobacter pylori in the stomach) or autoimmune disease (eg, Sjögren syndrome and salivary glands). Several chromosomal translocations were also identified in EMZL, accounting in the aggregate for approximately one-third of all cases. SMZL accounts for approximately 20% of all MZLs. Patients typically present with an enlarged spleen and involvement of abdominal lymph nodes and BM. Approximately 40%-50% of SMZLs are associated with deletions of chromosome 7q. NMZL is the less common entity, representing approximately 10% of all MZLs. Patients with NMZL, by definition, have lymph node–based disease without involvement of the spleen or extranodal sites. The molecular pathogenesis of NMZL is still unknown.
The prevalent predicament of relapsed acute myeloid leukemia
Authors: Szer Jeffrey 
Published: October 2019

Abstract
A majority of patients with acute myeloid leukemia (AML) will relapse after achieving complete remission. At relapse, patients should be risk stratified and a decision made about the appropriateness of intensive therapy and whether a potentially curative allogeneic stem cell transplantation (allo-SCT) is possible. Risk factors include duration of first complete remission and adverse cytogenetics, as well as age and FLT3 mutation status. Available therapies are steadily increasing, but for the most part should be regarded as either best palliation or as a bridge to allo-SCT. Simple symptomatic therapies for patients with extreme age or the worst prognosis should also be considered. Newer therapeutic options include novel cytotoxic chemotherapies including clofarabine, immunomodulatory agents, targeted therapies against FLT3 and mTOR, and immunoconjugates. All patients with relapsed AML should be considered for an appropriate clinical trial.
Is my patient a bleeder? A diagnostic framework for mild bleeding disorders
Authors: Quiroga Teresa , Mezzano Diego 
Published: October 2019

AbstractCongenital mild bleeding disorders (MBDs) are very prevalent and are the source of frequent diagnostic problems. Most MBDs are categorized as disorders of primary hemostasis (ie, type 1 VWD and platelet function disorders), but mild or moderate deficiencies of clotting factors and some rare hyperfibrinolytic disorders are also included. These patients have abnormal bleeding from the skin and mucous membranes, menorrhagia, and disproportionate hemorrhages after trauma, invasive procedures, and surgery. This review addresses the main problems that physicians and hemostasis laboratories confront with the diagnosis of these patients, including: discerning normal/appropriate from pathological bleeding, the role and yield of screening tests, the lack of distinctive bleeding pattern among the different diseases, the inherent difficulties in the diagnosis of type 1 VWD and the most common platelet functional disorders, improvements in assays to measure platelet aggregation and secretion, and the evidence that most of the patients with MBDs end up without a definite diagnosis after exhaustive and repeated laboratory testing. Much research is needed to determine the pathogenesis of bleeding in MBD patients. Better standardization of current laboratory assays, progress in the knowledge of fibrinolytic mechanisms and their laboratory evaluation, and new understanding of the factors contributing to platelet-vessel wall interaction, along with the corresponding development of laboratory tools, should improve our capacity to diagnose a greater proportion of patients with MBDs.
Malignant or benign leukocytosis
Authors: George Tracy I. 
Published: October 2019

AbstractLeukocytosis, or elevated WBC count, is a commonly encountered laboratory finding. Distinguishing malignant from benign leukocytosis is a critical step in the care of a patient, which initiates a vastly different decision tree. Confirmation of the complete blood cell count and the WBC differential is the first step. Examination of the PB smear is essential to confirming the automated blood cell differential or affirming the manual differential performed on the PB smear. Next is separation of the leukocytosis into a myeloid versus a lymphoid process. Distinguishing a reactive lymphoid proliferation from a lymphoproliferative disorder requires examination of lymphocyte morphology for pleomorphic lymphocytes versus a monomorphic population, with the latter favoring a lymphoproliferative neoplasm. Samples suspicious for lymphoproliferative disorders can be confirmed and characterized by flow cytometry, with molecular studies initiated in select cases; precursor lymphoid neoplasms (lymphoblasts) should trigger a BM examination. Myeloid leukocytosis triggers a differential diagnosis of myeloid leukemoid reactions versus myeloid malignancies. The manual differential is key, along with correct enumeration of blasts and blast equivalents, immature granulocytes, basophils, and eosinophils and identifying dysplasia to identify myeloid malignancies. Confirmation and characterization of myeloid malignancies should be performed with a BM examination and the appropriate ancillary studies. Myeloid leukemoid reactions commonly result from infections and show activated neutrophil changes on morphology; these should prompt evaluation for infection. Other causes of reactive myeloid leukocytoses are also discussed herein.
Assessment and management of massive bleeding: coagulation assessment, pharmacologic strategies, and transfusion management
Authors: Callum Jeannie L. , Rizoli Sandro 
Published: October 2019

AbstractThis review details the current knowledge in massive hemorrhage with regard to the pathophysiology and laboratory assessment of the coagulation disturbance, the role of plasma and platelet transfusion, the role of pharmaceutical strategies, and the clinical value of having a massive transfusion protocol. The bulk of the recent medical literature on this topic stems from the study of military and civilian trauma; however, where applicable, reference to postcardiac and post-noncardiac surgery and postpartum hemorrhage will also be discussed.
Small-molecule inhibitors in myeloproliferative neoplasms: are we aiming for the right targets?
Authors: Constantinescu Stefan N. , Vainchenker William 
Published: October 2019

AbstractThe ATP-binding pocket of the kinase domain of JAK2 is the major target of the present treatment of myeloproliferative neoplasms. Several inhibitors of JAK2 that are ATP competitive have been developed, but they do not discriminate between wild-type and mutant JAK2. These inhibitors have been used in myelofibrosis and, for the first time, treatment induced a reduction in spleen size and in constitutional symptoms. However, no dramatic effects on BM fibrosis, allele burden, or peripheral blast numbers were observed. These data indicate that other avenues should be explored that would either target mutant molecules (JAKs or receptors) more specifically and spare wild-type JAK2 or that would address other pathways that contribute to the malignant proliferation. Future success in treating myeloproliferative neoplasms will depend on advances of the understanding of JAK-STAT signaling and also on a better understanding of the disease pathogenesis, especially the role that mutants in spliceosome factors and epigenetic regulators play in the phenotype of the disease and the precise mechanism of fibrosis development.
Interpreting new molecular genetics in myelodysplastic syndromes
Authors: Abdel-Wahab Omar , Figueroa Maria E. 
Published: October 2019

Abstract
The myelodysplastic syndromes (MDS) are a clinically and cytogenetically heterogeneous group of clonal diseases characterized by ineffective hematopoiesis, peripheral blood cytopenias, and an increased risk of progression to acute myeloid leukemia. The precise molecular mechanisms behind the development of MDS have remained elusive; however, the distinct sensitivity of this disease to DNA methyltransferase inhibitors and the presence of markedly abnormal epigenetic profiles suggested the existence of an epigenetic mechanism underlying the disease. Recently, the advent of new technologies for the detection of genetic abnormalities has led to the description of a set of novel recurrent mutations in patients with this disease. The majority of these novel mutations have been described in genes encoding different components of the epigenetic machinery, many of which are associated with distinct clinical outcomes. Finally, mutations in mRNA splicing genes have also been described recently in MDS, underscoring the molecular complexity that underlies the development of this heterogeneous disease.
Are you sure this is Waldenström macroglobulinemia?
Authors: Ghobrial Irene M. 
Published: October 2019

AbstractWaldenström macroglobulinemia (WM) is a rare lymphoproliferative disorder characterized by the presence of lymphoplasmacytic cells in the BM and IgM monoclonal protein in the serum. The origin of the malignant clone is thought to be a B cell arrested after somatic hypermutation in the germinal center and before terminal differentiation to plasma cells. In this review, recent advances in the genetic and epigenetic regulators of tumor progression are discussed. Risk factors include IgM-monoclonal gammopathy of undermined significance, familial disease, and immunological factors. The clinical manifestations of the disease include those related to clonal infiltration of the BM, lymph nodes, and, rarely, other sites such as pulmonary or CNS infiltration (Bing-Neel syndrome). Other manifestations are related to the IgM monoclonal protein, including hyperviscosity, cryoglobulinemia, protein-protein interactions, Ab-mediated disorders such as neuropathy, hemolytic anemia, and Schnitzler syndrome. IgM deposition in organs can lead to amyloidogenic manifestations in WM. The diagnostic workup for a patient with WM and rare presentations of WM are described herein. Prognosis of WM depends on 5 major factors in the International Staging System, including age, anemia, thrombocytopenia, β-2 microglobulin, and IgM level. The differential diagnosis of WM includes IgM-multiple myeloma, marginal zone lymphoma, mantle cell lymphoma, and follicular lymphoma.
New insights into genotype and phenotype of VWD
Authors: Flood Veronica H. 
Published: October 2019

AbstractRecent advances in VWD research have improved our understanding of the genotype and phenotype of VWD. The VWF gene is highly polymorphic, with a large number of sequence variations reported in healthy individuals. This can lead to some difficulty when attempting to discern genotype–phenotype correlations because sequence variations may not represent disease. In type 1 VWD, mutations can be found throughout the VWF gene, but likely pathogenic sequence variations are found in only ∼2/3 of type 1 VWD patients. Sequence variations in type 2 VWD are located in the region corresponding to the defect in the VWF protein found in each type 2 variant. In type 3 VWD, sequence variations are not confined to a specific region of the VWF gene and also include large deletions that may not be picked up using conventional sequencing techniques. Use of genetic testing may be most helpful in diagnosis of type 2 VWD, in which a larger number of known, well characterized mutations are present and demonstration of one of these may help to confirm the diagnosis. Bleeding symptoms in general are more severe with decreasing VWF levels and more severe in type 2 and type 3 VWD compared with type 1 VWD. Prediction of phenotype for an individual patient, however, is still difficult, and the addition of genetic data will be most helpful in ascertaining the correct diagnosis for VWD patients.
Advances in therapies for non-Hodgkin lymphoma in children
Authors: Kobos Rachel , Terry William 
Published: October 2019

AbstractPediatric 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.
Treatment of Langerhans cell histiocytosis: role of BRAF/MAPK inhibition
Authors: Abla Oussama , Weitzman Sheila 
Published: October 2019

AbstractLangerhans 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.
Prolonged survival with the early use of a novel extracorporeal photopheresis regimen in patients with Sézary syndrome
Authors: Gao Crystal , McCormack Christopher , van der Weyden Carrie , Goh Michelle S. , Campbell Belinda A. , Twigger Robert , Buelens Odette , Harrison Simon J. , Khoo Christine , Lade Stephen , Prince H. Miles 
Published: October 2019

Abstract
Gao et al report that early use of extracorporeal photopheresis improves time to next treatment and survival in patients with Sézary syndrome.
PRIMARY CONGENITAL AND SECONDARY ACQUIRED SPLENIC PANHEMATOPENIA
Authors: DOAN CHARLES A. , WRIGHT CLAUDE-STARR 
Published: October 2019

Abstract
1. The spleen is an organ of multiple structures and many functions, but in the interests of human health and disease, it is probably far more important pathologically than physiologically.
2. It has been abundantly proved that instability in splenic functional balance toward any one of the essential elements of the blood passing through this organ may be an inherited trait, as in congenital hemolytic icterus. Recognition is now made of a syndrome in which, despite intensive compensatory panmyeloid hyperplasia, indiscriminate elimination of all circulating elements occurs, actually simulating panmyeloid hypoplasia. Splenectomy in such a syndrome is often dramatically curative. "Primary splenic panhematopenia" is suggested as an appropriate descriptive designation.
3. The potentially important role which may be played by the spleen, secondarily involved in a wide variety of syndromes, with the precipitation of varying degrees of peripheral cellular disequilibria, demands careful diagnostic discrimination. A dependable experience in the specific technics by which bone marrow and splenic functions are appraised is essential to sound judgment and clinical acumen.
4. The normal spleen is apparently not essential to life and health at any age and, therefore, may be surgically removed without prejudice to future hemolytopoietic equilibria and longevity. The pathologic spleen may at times constitute a very real hazard to health and an actual threat to survival; in the more acute syndromes, prompt surgical intervention may be lifesaving.
PROGNOSIS IN THE NEUROLOGIC MANIFESTATIONS OF PERNICIOUS ANEMIA
Authors: RUNDLES R. WAYNE 
Published: October 2019

Abstract
Four types of disturbed neurologic function occur in pernicious anemia: (1) cerebral, (2) olfactory, (3) peripheral nerve and posterior columns of the spinal cord, and (4) lateral columns of the spinal cord. The neurologic prognosis depends upon the specific type of disability present, its severity, duration, and the adequacy of treatment. With intensive use of highly potent liver extracts intramuscularly the prognosis is far better than generally recognized. Serious neurologic residuals can be avoided if the diagnosis is made reasonably early.