bluuebunny/crossref_metadata_2025 huggingface dataset:
Feeling Empathically Toward Other People and the Self: The Role of Perspective Shifting in Emotion Sharing and Self-Reassurance
Authors: Chiu Chui-De , Ng Hau Ching , Kwok Wing Ki , Tollenaar Marieke S.
Published: October 2019

Feeling one’s own emotions empathically when negative thoughts about the self arise, a defining element of self-reassurance, promotes resilience to prolonged emotional reactivity. We propose that feeling empathically toward the self is accomplished by first stepping into the shoes of an objectified, undesired self-aspect, after which the process of perspective shifting should be completed by reengaging the self to experience the moment in the first person. We hypothesize that the resumption of the egocentric perspective in perspective shifting, a cognitive characteristic of sharing other people’s emotions, is crucial for self-reassurance as well. The relationships among flexibility in perspective shifting, self-reassurance, and emotion sharing were examined in community participants. Our results show that quickly switching back to a visuospatial egocentric perspective after adopting an opposing perspective relates to self-reassurance and emotion sharing. We conclude that both reassuring the self and empathizing with other people involve flexibility in perspective shifting.
Research on corrosion behavior and biocompatibility of a porous Mg–3%Zn/5%β-Ca3(PO4)2 composite scaffold for bone tissue engineering
Authors: Tang Mingying , Yan Yang , OuYang Jianan , Yu Kun , Liu Congcong , Zhou Xiaohua , Wang Zhenting , Deng Youwen , Shuai Cijun
Published: October 2019

Background:

Rapid corrosion rates are a major impediment to the use of magnesium alloys in bone tissue engineering despite their good mechanical properties and biodegradability. Zinc is a promising alloy element, and it is an effective grain refiner for magnesium. β-Ca3(PO4)2 (β-TCP) is widely used for bone regeneration because of its good biocompatibility, and it also has a similar chemical and crystal structure to human bone.

Methods:

In this research, the magnesium alloy was reinforced by adding 3%Zn (wt.%) and 5%β-TCP (wt.%) particles in order to improve the corrosion resistance and biocompatibility. Furthermore, the biomaterial was prepared through powder metallurgy technology using NH4HCO3 as space-holding particles to construct porous Mg–3%Zn/5%β-TCP scaffolds.

Results:

The results revealed that the magnesium-zinc phase and calcium phosphate phase were uniformly distributed in the α-magnesium matrix. Mechanical and corrosion tests indicated that the scaffolds had mechanical strengths similar to that of human bone, and their corrosion resistance decreased with an increase in the porosity. The scaffolds had cytotoxicity grades of 0–1 against MG63 cells, SaoS2 cells, and HK-2 cells, which suggested that they were appropriate for cellular applications. In addition, the scaffolds demonstrated excellent biocompatibility when tested in rabbits.

Conclusions:

These results indicate that porous Mg–3%Zn/5%β-TCP scaffolds are promising biodegradable implants for bone tissue engineering.
Effect of cervical flexion and extension on thoracic sagittal alignment
Authors: Konishi Takamitsu , Endo Kenji , Aihara Takato , Matsuoka Yuji , Suzuki Hidekazu , Takamatsu Taichiro , Kusakabe Takuya , Sawaji Yasunobu , Nishimura Hirosuke , Murata Kazuma , Yamamoto Kengo
Published: October 2019

Introduction:

The cervical spine has the largest sagittal motion in the whole spine, and cervical alignment affects the thoracic sagittal alignment. However, the effects of cervical flexion and extension on thoracic sagittal alignment have not been investigated in detail. The purpose of this study was to analyze the change of thoracic sagittal alignment following cervical flexion and extension.

Subjects and methods:

A total of 55 consecutive patients (42 men and 13 women; average age 49.1 years) who presented to our department with spinal degenerative disease between January 2016 and September 2017 were enrolled in our study. Subjects with a history of trauma, infection, tumor, inflammatory disease, ossification, or cervical deformities, and those who had undergone spinal surgery were excluded. The following parameters were analyzed: occipito-axial angle (O–C2), C2 slope (C2S), C2–C7 angle, T1 slope (T1S), thoracic kyphosis, T1–T4 angle, T5–T8 angle, T9–T12 angle, lumbar lordosis, sacral slope, pelvic tilt in cervical flexion, neutral, and extension.

Results:

Cervical flexion significantly decreased O–C2, C2–C7 angles and T1S, and increased C2S. Cervical extension conversely changed these parameters. At cervical flexion, the correlation of C2–C7 angle with thoracic parameters was maintained, except for the T1–T4 angle. At cervical extension, the correlation was observed with T1S and T1–T4 angle.

Conclusion:

Cervical flexion affects the T1S and T5–T8 angle, but there is no significant change in T1–T4 and T9 and lower spino-pelvic columns. This study suggests that T2–T4 can be considered as a stable distal end when cervical long fixation for corrective surgery is performed.
Ethical Challenges of HIV Partner Notification in Prisons
Authors: Culbert Gabriel J. , Earnshaw Valerie A. , Levy Judith A.
Published: October 2019

Partner services provide a safe and humane way for people living with HIV (PLWH) to alert their sex and/or drug-injecting partners to the possibility of HIV exposure and the need for HIV testing, yet little is known about the ethical challenges of delivering partner services in prisons. In this article, we consider 7 key ethical and methodological questions that should be considered when developing, testing, or implementing partner services in prison settings. These questions relate to the ethics of: (1) mandatory HIV testing, (2) health illiteracy, (3) level of prison staff involvement, (4) protecting confidentiality, (5) minimizing harm, (6) achieving equivalency with community standards of care, and (7) providing HIV prevention and treatment services to index patient and their partners. By assisting PLWH in prison to inform partners with whom they may have shared HIV exposure either before or during incarceration, partner services can help to identify cases of undiagnosed HIV infection for testing and linkage to medical care. The acceptability and effectiveness of a future partner services model for PLWH in prison depends critically on answering these 7 questions to assure the highest ethical standards of research and practice.
Evaluation of Nurses’ Knowledge and Attitude toward HIV-Infected Patients in Barbados
Authors: Huq K. A. T. M. Ehsanul , Moriyama Michiko , Harris Esther E. , Shirin Habiba , Rahman Md Moshiur
Published: October 2019

Background:

Continued assessment of nurses’ knowledge and attitude is necessary for improving their performance at workplace. We attempted to evaluate nurses’ knowledge and attitude toward HIV-infected patients and their underlying factors.

Methods:

We conducted a descriptive, cross-sectional study participated by 218 nurses and collected relevant data.

Results:

Majority (57.3%) of the nurses had 1 to 5 years of experience in the nursing job, and 78.4% of them were involved in the provision of direct care to HIV-infected individuals for ≤5 years, and only 6.4% for ≥11 years. The overall knowledge and attitude of the participants were good (3.25/5 and 3.42/5 scores, respectively). The knowledge regarding appropriate care of HIV-infected patients was significantly better among the registered nurses compared to nursing assistants (NA) with limited years of formal education (odds ratio [OR] = 0.37; 95% confidence interval [CI] = 0.20-0.69; P <.001). In the provision of care to the HIV-infected patients, the attitude of female participants was significantly better than the males (unadjusted OR = 0.18; 95% CI = 0.05-0.60; P = .01).

Conclusion:

Inclusion of relevant HIV- and AIDS-related topics in the curriculum for NAs and closely guided hands-on training of the nurses are likely to improve nurses’ knowledge and attitude toward the provision of care to HIV-infected individuals.
FreeHear: A New Sound-Field Speech-in-Babble Hearing Assessment Tool
Authors: Moore David R. , Whiston Helen , Lough Melanie , Marsden Antonia , Dillon Harvey , Munro Kevin J. , Stone Michael A.
Published: October 2019

Pure-tone threshold audiometry is currently the standard test of hearing. However, in everyday life, we are more concerned with listening to speech of moderate loudness and, specifically, listening to a particular talker against a background of other talkers. FreeHear delivers strings of three spoken digits (0–9, not 7) against a background babble via three loudspeakers placed in front and to either side of a listener. FreeHear is designed as a rapid, quantitative initial assessment of hearing using an adaptive algorithm. It is designed especially for children and for testing listeners who are using hearing devices. In this first report on FreeHear, we present developmental considerations and protocols and results of testing 100 children (4–13 years old) and 23 adults (18–30 years old). Two of the six 4 year olds and 91% of all older children completed full testing. Speech reception threshold (SRT) for digits and noise colocated at 0° or separated by 90° both improved linearly across 4 to 12 years old by 6 to 7 dB, with a further 2 dB improvement for the adults. These data suggested full maturation at approximately 15 years old SRTs at 90° digits/noise separation were better by approximately 6 dB than SRTs colocated at 0°. This spatial release from masking did not change significantly across age. Test–retest reliability was similar for children and adults (standard deviation of 2.05–2.91 dB SRT), with a mean practice improvement of 0.04–0.98 dB. FreeHear shows promise as a clinical test for both children and adults. Further trials in people with hearing impairment are ongoing.
Non-Hodgkin's Lymphoma: Molecular Features of B Cell Lymphoma
Authors: Macintyre Elizabeth , Willerford Dennis , Morris Stephan W.
Published: October 2019

The rapid increase in the incidence of the B cell non-Hodgkin's lymphomas (NHL) and improved understanding of the mechanisms involved in their development renders timely a review of the theoretical and practical aspects of molecular abnormalities in B cell NHL.

In Section I, Dr. Macintyre addresses the practical aspects of the use of molecular techniques for the diagnosis and therapeutic management of patients with B cell NHL. While detection of clonal Ig rearrangements is widely used to distinguish reactive from malignant lymphoproliferative disorders, molecular informativity is variable. The relative roles of cytogenetic, molecular and immunological techniques in the detection of genetic abnormalities and their protein products varies with the clinical situation. Consequently, the role of molecular analysis relative to morphological classification is evolving. Integrated diagnostic services are best equipped to cope with these changes. Recent evidence that large scale gene expression profiling allows improved prognostic stratification of diffuse large cell lymphoma suggests that the choice of diagnostic techniques will continue to change significantly and rapidly.

In Section II, Dr. Willerford reviews current understanding of the mechanisms involved in immunoglobulin (Ig) gene rearrangement during B lymphoid development and the way in which these processes may contribute to Ig-locus chromosome translocations in lymphoma. Recent insights into the regulation of Ig gene diversification indicate that genetic plasticity in B lymphocytes is much greater than previously suspected. Physiological genomic instability, which may include isotype switching, recombination revision and somatic mutation, occurs in germinal centers in the context of immune responses and may explain longstanding clinical observations that link immunity and lymphoid neoplasia. Data from murine models and human disorders predisposing to NHL have been used to illustrate these issues.

In Section III, Dr. Morris reviews the characteristics and consequences of deregulation of novel “proto-oncogenes” involved in B cell NHL, including PAX5 (chromosome 9p 13), BCL8 (15q11-q13), BCL9, MUC1, FcγRIIB and other 1q21-q22 genes and BCL10 (1p22). The AP12-MLT/MALT1 [t(11;18)(q21;q21)] fusion transcript is also described.
Viral Disease in Hematology
Authors: Franchini Genoveffa , Ambinder Richard F. , Barry Michèle
Published: October 2019

As part of the international outreach of the American Society of Hematology, this review addresses some aspects of the genetics, biology, epidemiology, and clinical relevance of viruses that cause a variety of hematopoietic disorders in human populations. The viruses described here have a different pattern of geographical distribution, and the disease manifestations may vary according to environmental and/or genetic characteristics of the host. Epstein-Barr virus, a linear double-stranded DNA virus (herpesvirus), and the human T-cell leukemia virus, a retrovirus with a single-stranded diploid RNA genome, are associated among other diseases with lymphoma and leukemia/lymphoma, respectively. Both viruses cause a lifelong infection, but only a small percentage of infected individuals develop hematopoietic neoplasms. Epidemiological data suggest that the time of infection may be important in determining disease outcome in both HTLV-I and EBV infection. The pathogenic mechanisms used by these viruses are of most interest since they may recapitulate growth dysregulation steps also occurring in other hematopoietic malignancies.

In Section I Dr. Franchini reviews the biology, genetics and diseases associated with HTLV-I and HTLV-II. In Section II, Dr. Ambinder reviews the biology of EBV infection and its relationship to the pathogenesis of Hodgkin's disease and other malignancies.

In Section III, Dr. Barry reviews the viral hemorrhagic fevers caused by RNA viruses such as Arenaviridae, Bunyaviridae, Filoviridae, and Flaviviridae, which can lead to acute syndromes that can be fatal. However, prompt diagnosis is key for patient management as well as for limiting their spread to others. These syndromes have become the focus of public concern and represent not only a clinical challenge, since in most cases no specific antiviral treatment is available, but also a challenge for future basic research on their biology and pathogenesis since little is known at present.
The 2008 WHO classification of lymphomas: implications for clinical practice and translational research
Authors: Jaffe Elaine S.
Published: October 2019

The 4th edition of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues published in 2008 builds upon the success of the 2001 3rd edition; new entities are defined, and solutions for problematic categories are sought. Recent studies have drawn attention to the biological overlap between classical Hodgkin lymphoma (CHL) and diffuse large B-cell lymphomas (DLBCL). Similarly, there is a greater appreciation of the borderlands between Burkitt lymphoma and DLBCL. Strategies for the management of these borderline lesions are proposed. Additionally, age-specific and site-specific factors play an important role in the definition of several new entities, which also have biological underpinnings. Among the peripheral T-cell lymphomas (PTCL), more precise definitions were introduced for several entities, including anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, enteropathy-associated T-cell lymphoma, and subcutaneous panniculitis-like T-cell lymphoma. Several new variants of primary cutaneous T-cell lymphomas are proposed. Finally, the subclassification and categorization of the most common lymphoma subtypes, follicular lymphoma (FL) and DLBCL, were altered to enhance diagnostic accuracy and aid in clinical management. The 2008 WHO classification also draws attention to early events in lymphomagenesis. These lesions help delineate the earliest steps in neoplastic transformation and generally mandate a conservative therapeutic approach. The 2001 classification was rapidly adopted for clinical trials and successfully served as a common language for scientists comparing genetic and functional data. The modifications made in the 2008 classification are the result of this successful partnership among pathologists, clinicians, and biologists, but are only a stepping stone to the future.
Immune Thrombocytopenia
Authors: Cuker Adam , Cines Douglas B.
Published: October 2019

Immune thrombocytopenia (ITP) comprises a heterogeneous group of disorders characterized by autoimmune-mediated platelet destruction and impairment of thrombopoiesis. ITP may occur in the absence of an evident predisposing etiology (primary ITP) or secondary to a growing list of associated conditions (secondary ITP), and must be differentiated from other causes of thrombocytopenia. This review focuses on primary ITP in adults. The traditional goal of therapy in this population is to achieve a hemostatic platelet count of 30 × 109/L or above for most patients while minimizing treatment-related morbidity. This approach has been called into question by the recent advent of well-tolerated and effective agents for the management of ITP, including pulse-dose dexamethasone, rituximab, and the thrombopoietin receptor agonists. Recent studies suggest the potential for aggressive therapy at the time of diagnosis to alter the natural history of ITP and point to the importance of quality-of-life considerations in therapeutic decision making.
Is going for cure in chronic myeloid leukemia possible and justifiable?
Authors: Mahon François-Xavier
Published: October 2019

After more than a decade of treatment of chronic myeloid leukemia (CML) patients with the BCR-ABL tyrosine kinase inhibitor imatinib, and despite the impressive clinical results of this targeted therapeutic, many questions remain unresolved. One major question is how to cure CML, and the next step for the future will be to address this key issue. CML is a good model of cancer. The fact that the majority of CML patients who respond very well but discontinue tyrosine kinase inhibitors later show evidence of molecular recurrence focuses attention on the need for further research on leukemic stem cells. The challenge now is to understand why, after stopping treatment, the leukemia recurs in some patients but not in others. If we win this battle, this progress will certainly benefit the treatment and management of other leukemias and solid tumors and will validate this new topic.
How to approach neutropenia
Authors: Boxer Laurence A.
Published: October 2019

Neutropenia is defined as the reduction in the absolute number of neutrophils in the blood circulation. Acute neutropenia is a relatively frequent finding, whereas disorders of production of neutrophils are quite rare. Acute neutropenia is often well tolerated and normalizes rapidly. Neutropenia arising as a result of underlying hematologic disorders is far more significant. Such a patient may be at risk for infectious complications and will likely require a thorough investigation. Acute neutropenia evolves over a few days and occurs when neutrophil use is rapid and production is impaired. Chronic neutropenia may last for 3 months or longer and is a result of reduced production, increased destruction, or excessive splenic sequestration of neutrophils. Neutropenia may be classified by whether it arises secondarily to causes extrinsic to BM myeloid cells, which is common; as an acquired disorder of myeloid progenitor cells, which is less frequent; or as an intrinsic defect arising from impaired proliferation and maturation of myeloid progenitor cells in the BM, which is rare. Severe neutropenia with absolute neutrophil counts below 500/μL increases susceptibility to bacterial or fungal infections. Multiple disorders of severe congenital neutropenia have been found by the discovery of genetic defects affecting differentiation, adhesion, and apoptosis of neutrophil precursors. Elucidation of the multiple genetic defects have provided insight into the biology of the cell involving membrane structures, secretory vesicles, mitochondrial metabolism, ribosome biogenesis, transcriptional regulation, and cytoskeletal dynamics, as well as the risk for myelodysplasia and acute myeloid leukemia.
The porphyrias: advances in diagnosis and treatment
Authors: Balwani Manisha , Desnick Robert J.
Published: October 2019

The inborn errors of heme biosynthesis, the porphyrias, are 8 genetically distinct metabolic disorders that can be classified as “acute hepatic,” “hepatic cutaneous,” and “erythropoietic cutaneous” diseases. Recent advances in understanding their pathogenesis and molecular genetic heterogeneity have led to improved diagnosis and treatment. These advances include DNA-based diagnoses for all the porphyrias, new understanding of the pathogenesis of the acute hepatic porphyrias, identification of the iron overload-induced inhibitor of hepatic uroporphyrin decarboxylase activity that causes the most common porphyria, porphyria cutanea tarda, the identification of an X-linked form of erythropoietic protoporphyria due to gain-of-function mutations in erythroid-specific 5-aminolevulinate synthase (ALAS2), and new and experimental treatments for the erythropoietic prophyrias. Knowledge of these advances is relevant for hematologists because they administer the hematin infusions to treat the acute attacks in patients with the acute hepatic porphyrias, perform the chronic phlebotomies to reduce the iron overload and clear the dermatologic lesions in porphyria cutanea tarda, and diagnose and treat the erythropoietic porphyrias, including chronic erythrocyte transfusions, bone marrow or hematopoietic stem cell transplants, and experimental pharmacologic chaperone and stem cell gene therapies for congenital erythropoietic protoporphyria. These developments are reviewed to update hematologists on the latest advances in these diverse disorders.
How to approach thrombocytopenia
Authors: Stasi Roberto
Published: October 2019

Thrombocytopenia is a common hematologic finding with variable clinical expression. A low platelet count may be the initial manifestation of infections such as HIV and hepatitis C virus or it may reflect the activity of life-threatening disorders such as the thrombotic microangiopathies. A correct identification of the causes of thrombocytopenia is crucial for the appropriate management of these patients. In this review, we present a systematic evaluation of adults with thrombocytopenia. The approach is clearly different between outpatients, who are frequently asymptomatic and in whom we can sometimes indulge in sophisticated and relatively lengthy investigations, and the dramatic presentation of acute thrombocytopenia in the emergency department or in the intensive care unit, which requires immediate intervention and for which only a few diagnostic tests are available. A brief discussion of the most common etiologies seen in both settings is provided.
The many faces of common variable immunodeficiency
Authors: Cunningham-Rundles Charlotte
Published: October 2019

Common variable immunodeficiency (CVID) is a rare immune deficiency characterized by low levels of serum IgG, IgA, and/or IgM, with a loss of Ab production. The diagnosis is most commonly made in adults between the ages of 20 and 40 years, but both children and much older adults can be found to have this immune defect. The range of clinical manifestations is broad, including acute and chronic infections, inflammatory and autoimmune diseases, and an increased incidence of cancer and lymphoma. For all of these reasons, the disease phenotype is both heterogeneous and complex. In the past few years, data from large patient registries have revealed that both selected laboratory markers and clinical phenotyping may aid in separating groups of subjects into biologically relevant categories. CVID consists of 2 phenotypes, 1 in which infections are the characteristic and another in which impressive inflammatory and/or hematologic complications also develop, including lymphadenopathy, splenomegaly, autoimmune cytopenias, enteropathy, and/or and granulomatous disease. These phenotypes appear to be stable, are related to immunologic and inflammatory markers, and are predictive of outcomes. This review outlines current understanding about this syndrome based on studies of large cohorts, highlighting the evaluation and treatment of complications and, in particular, the autoimmune and inflammatory conditions that affect these patients.
Pathogenesis in immune thrombocytopenia: new insights
Authors: Johnsen Jill
Published: October 2019

Idiopathic (immune) thrombocytopenic purpura (ITP) is a common autoimmune disorder resulting in isolated thrombocytopenia. ITP can present either alone (primary) or in the setting of other conditions (secondary) such as infections or altered immune states. ITP is associated with a loss of tolerance to platelet antigens and a phenotype of accelerated platelet destruction and impaired platelet production. Although the etiology of ITP remains unknown, complex dysregulation of the immune system is observed in ITP patients. Antiplatelet antibodies mediate accelerated clearance from the circulation in large part via the reticuloendothelial (monocytic phagocytic) system. In addition, cellular immunity is perturbed and T-cell and cytokine profiles are significantly shifted toward a type 1 and Th17 proinflammatory immune response. Further clues into immune dysregulation in ITP may be gleaned from studies of secondary ITP. Some infections can induce antiplatelet Abs by molecular mimicry, and there may be common elements involved in breaking tolerance with other autoimmune disorders. There is also evidence for a genetic predisposition to both ITP and responsiveness to therapy, which may in part lie within immune-related genes. Lastly, treatment with immunomodulatory agents remains the mainstay of ITP therapies.
What is the evidence for the use of bisphosphonate therapy in newly diagnosed multiple myeloma patients lacking bone disease?
Authors: Locke Frederick L. , Morgan Gareth J.
Published: October 2019

A 55-year-old man without prior medical problems presented to the emergency room with a 2-month history of progressive fatigue. Initial workup showed a hemoglobin level of 9.0 g/dL and an increased total protein level of 12.6 g/dL. Further testing revealed a normal serum calcium and creatinine, an IgG kappa paraprotein of 5.4 g/dL, and a Bence Jones proteinuria of 450 mg of kappa light chain in 24 hours. The bone marrow showed 60% plasma cells with normal cytogenetics and t(4;14), but no other associated genetic abnormalities by FISH. Skeletal survey and MRI of the spine were negative for myeloma bone disease. The patient's oncologist recently began therapy with lenalidomide, bortezomib, and dexamethasone and recommended the initiation of zoledronic acid monthly. The patient questions the benefit of this drug because he has no bone disease.
Interim PET-CT in the management of diffuse large B-cell lymphoma
Authors: Moskowitz Craig H.
Published: October 2019

Once the diagnosis of diffuse large B-cell lymphoma has been established, physicians and patients would like to know if a given treatment regimen is likely to succeed—if the patient can be cured or if at least a durable remission is achievable. This desire has lead to efforts to use interim positron emission tomography (PET) scanning as part of risk-adapted therapeutic clinical trials. In general, these studies use a variable number of doxorubicin-based induction cycles with rituximab, followed by the interim PET. If the test is negative, treatment is continued, but if it is positive, therapy is changed to treatment that concludes with autologous stem cell transplantation. Results of studies for interim PET have yielded mixed and confusing results, with high negative predictive value but positive predictive value ranging from 20%-80%. To use interim PET scanning effectively, clinicians need simple (positive or negative) criteria that are easy to interpret, reproducible, and have a high positive and negative predictive value so that we can be certain that by not changing therapy if the test is positive, we are not doing the patient a disservice.
Is there any role for transplantation in the rituximab era for diffuse large B-cell lymphoma?
Authors: Gisselbrecht Christian
Published: October 2019

Salvage chemotherapy followed by high-dose therapy and autologous stem cell transplantation is the standard of treatment for chemosensitive relapses in diffuse large B-cell lymphoma. The addition of rituximab to chemotherapy has improved the response rate and failure-free survival after first-line treatment and relapses. Fewer relapses are expected, although there is no consensus on the best salvage regimen. The intergroup Collaborative Trial in Relapsed Aggressive Lymphoma (CORAL) set the limits for this standard of treatment after first comparing 2 salvage regimens: rituximab, ifosfamide, etoposide, and carboplatin (R-ICE) and rituximab, dexamethasone, aracytine, and cisplatin (R-DHAP). There was no difference in response rates or survivals between these salvage regimens. Several factors affected survival: prior treatment with rituximab, early relapse (< 12 months), and a secondary International Prognostic Index score of 2-3. For patients with 2 factors, the response rate to salvage was only 46%, which identified easily a group with poor outcome. Moreover, patients with an ABC subtype or c-MYC translocation responded poorly to treatment. More than 70% of patients will not benefit from standard salvage therapy, and continued progress is needed. Studies evaluating immunotherapy after transplantation, including allotransplantation, new conditioning regimens with radioimmunotherapy and other combinations of chemotherapy based on diffuse large B-cell lymphoma subtype, are discussed herein. Early relapses and/or patients refractory to upfront rituximab-based chemotherapy have a poor response rate and prognosis. A better biological understanding of these patients and new approaches are warranted.
Changing role of stem cell transplantation in follicular lymphoma
Authors: Laport Ginna G.
Published: October 2019

Patients with advanced follicular lymphoma (FL) have numerous treatment options, including observation, radiotherapy, single-agent or combination chemotherapy, mAbs, and radioimmunoconjugates. These therapies can extend progression-free survival but none can provide a cure. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curable therapy for FL, with the field shifting more toward the use of reduced-intensity conditioning regimens because of the lower associated nonrelapse mortality compared with myeloablative regimens. However, GVHD and infection are still problematic in the allo-HSCT population. Autologous HSCT (auto-HSCT) confers high response rates and prolongs progression-free survival in relapsed patients who are chemosensitive, and an increasing amount of data suggest that auto-HSCT may be curative if offered to relapsed patients who are not heavily pretreated. Auto-HSCT has no role as consolidation therapy for patients in first remission based on the results from 3 large randomized trials. Novel conditioning regimens with radioimmunoconjugates have been used in both auto-HSCT and allo-HSCT regimens and results have shown efficacy even in chemorefractory patients. Therefore, with the exception of patients in first remission, the optimal timing for HSCT remains controversial. However, the outcomes seen after auto-HSCT and allo-HSCT continue to improve, and HSCT represents a treatment modality that should be considered in all FL patients, especially while their disease remains chemoresponsive.
Platelets in the neonatal period: developmental differences in platelet production, function, and hemostasis and the potential impact of therapies
Authors: Sola-Visner Martha
Published: October 2019

Thrombocytopenia is a common problem among sick neonates admitted to the neonatal intensive care unit. Frequently, platelet transfusions are given to thrombocytopenic infants in an attempt to decrease the incidence or severity of hemorrhage, which is often intracranial. Whereas there is very limited evidence to guide platelet transfusion practices in this population, preterm infants in the first week of life (the highest risk period for bleeding) are nearly universally transfused at higher platelet counts than older infants or children. To a large extent, this practice has been influenced by the observation that neonatal platelets are hyporeactive in response to multiple agonists in vitro, although full-term infants exhibit normal to increased primary hemostasis. This apparently paradoxical finding is due to factors in the neonatal blood that enhance the platelet-vessel wall interaction and counteract the platelet hyporeactivity. Relatively few studies have evaluated the platelet function and primary hemostasis of preterm infants, the subset of neonates at highest risk of bleeding and those most frequently transfused. Current understanding of platelet production and function in preterm and full-term neonates, how these factors affect their response to thrombocytopenia and their primary hemostasis, and the implications of these developmental differences to transfusion medicine are reviewed herein.
New oral anticoagulants: which one should my patient use?
Authors: Weitz Jeffrey I. , Gross Peter L.
Published: October 2019

The new oral anticoagulants are rapidly replacing warfarin for several indications. In contrast to warfarin, which lowers the functional levels of all of the vitamin K-dependent clotting factors, the new agents target either factor Xa or thrombin. With targeted inhibition of coagulation, the new oral anticoagulants have pharmacologic and clinical features that distinguish them from warfarin. Focusing on these features, this paper (a) compares the pharmacology of the new oral anticoagulants with that of warfarin (b) identifies the class effects of these drugs and their differentiating features, (c) reviews their current indications, and (d) uses this information to help clinicians make informed decisions regarding the choice of the right anticoagulant for the right patient.
The spectrum of JAK2-positive myeloproliferative neoplasms
Authors: Kiladjian Jean-Jacques
Published: October 2019

The discovery of the JAK2V617F mutation triggered an unexpected flowering of basic and clinical studies in the field of myeloproliferative neoplasms (MPNs), resulting after just a few years in an exceptional amount of new information. One important consequence of those new findings was the modification of the World Health Organization classification and diagnostic algorithms for these diseases, which is still based on the original concept developed by William Dameshek in 1951 and keeps distinct entities under the umbrella of classical Philadelphia-negative MPNs. These MPNs are essential thrombocythemia, polycythemia vera, and primary myelofibrosis. Could a new molecular classification be a better tool to manage MPN patients? Several studies have shown that essential thrombocythemia and primary myelofibrosis can be divided into distinct subtypes based on the presence of the JAK2V617F mutation. Can we now define JAK2-positive diseases to depict a distinct entity from JAK2-negative MPNs? This chapter reviews the significance of JAK2 mutation positivity in the diagnosis, prognosis, and therapy of MPNs.
Is there a role for the use of IFN-α in primary myelofibrosis?
Authors: Nguyen Huong (Marie) , Kiladjian Jean-Jacques
Published: October 2019

A 62-year-old man with a history of diabetes and hypertension is referred to your hematology clinic for an incidental discovery of anemia. He does not have any constitutional symptoms and previous blood counts have been within the normal range. He has hepatosplenomegaly with a palpable spleen of 6 cm below the left costal margin and a liver size of 2.5 cm below the right costal margin. Laboratory evaluation shows a WBC count of 12.8 K/μL, hemoglobin of 11.0 g/dL, and platelets of 202 K/μL, with a mean corpuscular volume of 85.7, 72% neutrophils, 13% lymphocytes, 4% monocytes, 5% eosinophils, 1% basophils, 1% promyelocytes, 4% myelocytes, and lactate dehydrogenase of 447 U/L (upper limit of normal is < 340 U/L). Peripheral blood smear shows 2+ teardrop-shaped RBCs, large hypogranular platelets, and rare nucleated RBCs. Bone marrow (BM) biopsy exhibits a hypercellular BM with atypical megakaryocytes and increased reticulin fibrosis (MF-1). BCR-ABL gene rearrangement by FISH was negative and JAK2 V617F mutation was 95% positive. He was diagnosed with primary myelofibrosis considered low risk (risk score of 0) by the International Prognostic Scoring System.1 Because he is low risk and asymptomatic, he does not need treatment at this time.2 However, he has read about the possible clinical benefits of IFN-α and its potential reduction of BM fibrosis and wonders whether this would be an appropriate treatment.
Diagnostic and therapeutic challenges in the thrombotic thrombocytopenic purpura and hemolytic uremic syndromes
Authors: George James N. , Al-Nouri Zayd L.
Published: October 2019

Evaluation and management of patients with suspected thrombotic thrombocytopenic purpura (TTP) continue to be a critical challenge for hematologists. The diagnostic criteria are not precise, often causing uncertainty about whether it is appropriate to initiate plasma exchange (PEX), the essential treatment for TTP. Initiation of PEX remains a clinical decision; severe ADAMTS13 (< 10% activity) deficiency alone is neither sufficiently sensitive nor specific for the diagnosis of TTP. However, patients who do have severe acquired ADAMTS13 deficiency define the characteristic clinical features of TTP, the response to treatment, and the long-term outcomes. Patients with severe acquired ADAMTS13 deficiency are predominantly young women and the relative frequency of blacks is increased. Patients may present with only microangiopathic hemolytic anemia and thrombocytopenia, neurologic and renal abnormalities are often not present, fever rarely occurs; the complete “pentad” of these clinical features almost never occurs in current practice. Response to PEX is typically rapid but may not be sustained when PEX is stopped. Use of corticosteroids and rituximab has decreased the number of PEX treatments required to achieve a remission and has resulted in fewer PEX-related major complications. Relapse (in approximately 40% of patients) may be the most apparent risk after recovery, but long-term health outcomes are also very important. Minor cognitive abnormalities are common, the frequency of depression is increased, and the frequency of hypertension is increased. Careful long-term follow-up of TTP patients is essential.
Implications of new prognostic markers in chronic lymphocytic leukemia
Authors: Chiorazzi Nicholas
Published: October 2019

Several prognostic markers based on genetic, phenotypic, and molecular characteristics of chronic lymphocytic leukemia (CLL) B cells have emerged in the past decade. The clinical utility of these newer prognostic indicators, alone or in combination with each other and other clinical predictive systems, is still being determined. This chapter attempts to define biologic and molecular underpinnings of 3 sets of prognostic indicators in CLL: genetic abnormalities quantified by FISH and/or defined by exploratory sensitive molecular techniques, expression of specific proteins in or on CLL cells (ie, CD38, CD49d, and ZAP-70), and the IGHV mutation status of a CLL clone. Although not demonstrated conclusively, each probably reflects the biologic properties of the leukemic cells of individual CLL patients. This reflection may be direct, indicating a specific property of the CLL cell itself, or indirect, representing how the CLL cell interacts with the host's microenvironment. The new tyrosine kinase inhibitors that are currently in clinical trials support this interpretation. These and other biology-based indicators of patient clinical course and outcome can be used as starting points from which to understand and treat CLL.
JAK inhibition in the myeloproliferative neoplasms: lessons learned from the bench and bedside
Authors: Gotlib Jason
Published: October 2019

The discovery of the JAK2 V617F mutation in the classic BCR-ABL1–negative myeloproliferative neoplasms in 2005 catalyzed a burst of research efforts that have culminated in substantial dividends for patients. Beyond JAK2 V617F, a more detailed picture of the pathobiologic basis for activated JAK-STAT signaling has emerged. In some patients with myelofibrosis (MF), next-generation sequencing technologies have revealed a complex clonal architecture affecting both genetic and epigenetic regulators of cell growth and differentiation. Although these bench-top findings have informed the clinical development of JAK inhibitors in MF, they have also provided scientific context for some of their limitations. The JAK1/JAK2 inhibitor ruxolitinib is approved for treatment of MF in North America and Europe and other lead JAK inhibitors discussed herein (fedratinib [SAR302503], momelotinib [CYT387], and pacritinib [SB1518]), have entered advanced phases of trial investigation. Uniformly, these agents share the ability to reduce spleen size and symptom burden. A major challenge for practitioners is how to optimize dosing of these agents to secure clinically relevant and durable benefits while minimizing myelosuppression. Suboptimal responses have spurred a “return to the bench” to characterize the basis for disease persistence and to inform new avenues of drug therapy.
Monitoring and reversal of direct oral anticoagulants
Authors: Cuker Adam , Siegal Deborah
Published: October 2019

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.
Uncommon histiocytic disorders: Rosai–Dorfman, juvenile xanthogranuloma, and Erdheim–Chester disease
Authors: Haroche Julien , Abla Oussama
Published: October 2019

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.
FURTHER OBSERVATIONS ON THE EFFECT OF BENZENE ON A STRAIN OF MYELOID CHLOROLEUKEMIA IN MICE AND ON CHANGES PRODUCED IN THE LEUKEMIC CELLS BY THE CHEMICAL
Authors: FLORY C. M. , STEINHARDT I. D. , FURTH J.
Published: October 2019

Oral administration of 5 mg. of benzene six times weekly to 46 mice that had been injected 24 hours before with the cells of the myeloid chloroleukemia 1394, considerably prolonged the survival of the animals, and in 16 of these mice it seemed to prevent the development of the disease. The spleens of the animals so treated increased in size at a much slower rate than those of the untreated animals, and the leukemic infiltration of the organs was delayed.

Five mg. of benzene given in a similar manner to mice with advanced chloroleukemia likewise prolonged the survival time of the mice and also slowed the rate of increase of the size of the spleens; 25 mg. given five times in a 6 day period to mice with this leukemia brought about a marked reduction in the size of the spleens. Further treatments slowed the rate of enlargement of the spleens and survival was prolonged.

In 8 mice bearing subcutaneous tumors composed of the cells of the chloroleukemia the oral administration of 25 mg. of benzene five times in a 6 day period followed by 5 mg. given six times weekly brought about the disappearance of the local tumors as determined by palpation, but in 6 mice the tumors recurred and killed the animals. Microscopic examination of tumors of mice treated with benzene showed advanced degenerative changes in leukemic cells.
A Histochemical Procedure for Localizing and Evaluating Leukocyte Alkaline Phosphatase Activity in Smears of Blood and Marrow
Authors: KAPLOW LEONARD S.
Published: October 2019

A rapid and simple method is described for demonstrating the presence of alkaline phosphatase activity in cells of blood and bone marrow. Smears were fixed with 10 per cent formalin in methanol at 0 ± 5 C. for 30 seconds and stained by the azo dye procedure, using propanediol buffer at a pH of 9.6.

A "scoring" technic is outlined, which permits the comparison of alkaline phosphatase activities of blood leukocytes of different individuals.

Alkaline phosphatase activity was found only in neutrophilic granulocytes and was localized exclusively in the cytoplasm of these cells. In normal adults, 43 to 95 per cent (mean of 78%) of all neutrophils were unstained. Staining was up to ten times more intense in smears from patients with a variety of pathologic disorders.