bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Polycythemia Vera Update: Diagnosis, Pathobiology, and Treatment
Authors: Pearson Thomas C. , Messinezy Maria , Westwood Nigel , Green Anthony R. , Bench Anthony J. , Green Anthony R. , Huntly Brian J.P. , Nacheva Elizabeth P. , Barbui Tiziano , Finazzi Guido 
Published: October 2019

AbstractThis review focuses on polycythemia vera (PV)—its diagnosis, cellular and genetic pathology, and management. In Section I, Dr. Pearson, with Drs. Messinezy and Westwood, reviews the diagnostic challenge of the investigation of patients with a raised hematocrit. The suggested approach divides patients on their red cell mass (RCM) results into those with absolute (raised RCM) and apparent (normal RCM) erythrocytosis. A standardized series of investigations is proposed for those with an absolute erythrocytosis to confirm the presence of a primary (PV) or secondary erythrocytosis, with abnormal and normal erythropoietic compartments respectively, leaving a heterogenous group, idiopathic erythrocytosis, where the cause cannot be established. Since there is no single diagnostic test for PV, its presence is confirmed following the use of updated diagnostic criteria and confirmatory marrow histology.In Section II, Dr. Green with Drs. Bench, Huntly, and Nacheva reviews the evidence from studies of X chromosome inactivation patterns that support the concept that PV results from clonal expansion of a transformed hemopoietic stem cell. Analyses of the pattern of erythroid and myeloid colony growth have demonstrated abnormal responses to several cytokines, raising the possibility of a defect in a signal transduction pathway shared by several growth factors. A number of cytogenetic and molecular approaches are now focused on defining the molecular lesion(s).In the last section, Dr. Barbui with Dr. Finazzi addresses the complications of PV, notably thrombosis, myelofibrosis and acute leukemia. Following an evaluation of published data, a management approach is proposed. All patients should undergo phlebotomy to keep the hematocrit (Hct) below 0.45, which may be all that is required in those at low thrombotic risk and with stable disease. In those at high thrombotic risk or with progressive thrombocytosis or splenomegaly, a myelosuppressive agent should be used. Hydroxyurea has a role at all ages, but 32P or busulfan may be used in the elderly. In younger patients, interferon-α or anagrelide should be considered. Low-dose aspirin should be used in those with thrombotic or ischemic complications.
New Developments in the Therapy of Acute Myelocytic Leukemia
Authors: Gorin Norbert C. , Estey Elihu , Jones Richard J. , Levitsky Hyam I. , Borrello Ivan , Slavin Shimon 
Published: October 2019

AbstractCurrent conventional treatment for patients with acute myelogenous leukemia results in a high percentage of clinical responses in most patients. However, a high percentage of patients still remain refractory to primary therapy or relapse later. This review examines the search for new agents and new modes of therapy. In Section I, Dr. Estey discusses new agents directed at various targets, such as CD33, angiogenesis, inappropriately methylated (suppressor) genes, cell cycle checkpoints, proteosomes, multidrug resistance (MDR) gene, mitochondrial apoptotic pathway. He also reviews preliminary results of phase I trials with the nucleoside analog troxacitabine and liposomal anthracyclin and suggests new strategies for trials of new agents.In Section II, Dr. Jones revisits differentiation therapy and presents results of preclinical and clinical studies that demonstrate that a variety of clinically applicable cell cycle inhibitors (interferon, phenylbutyrate, vitamin D, retinoids, bryostatin-1) preferentially augments growth factor-mediated induction of myeloid leukemia terminal differentiation, as well as blocks growth factors' effects on leukemia proliferation. The combination of cell cycle inhibition plus myeloid growth factors may offer a potential treatment for resistant myeloid leukemias.In Section III, Drs. Levitsky and Borrello address the question of tumor vaccination in AML and shows that, although tumor rejection antigens in AML have not been formally identified to date, a growing number of attractive candidates are ripe for testing with defined antigen-specific vaccine strategies. Interestingly, the ability to drive leukemic blasts to differentiate into competent antigen presenting cells such as dendritic cells may be exploited in the creation of cellular vaccines. Ultimately, the successful development of active immunotherapy for AML will require integration with dose-intensive chemotherapy, necessitating a more complete understanding of host immune reconstitution.In Section IV, Dr. Slavin reviews the concept of delivering non-myeloablative stem cell transplantation (NST) and delayed lymphocyte infusion (DLI) to increase tolerance in particular in high risk and older patients, and take advantage of the graft-versus-leukemia (GVL) effect.All these approaches hold promise in reducing morbidity and mortality and differ from the older concepts aiming at delivering the highest possible doses of chemotherapy and/or total body irradiation to reach maximum leukemia cell kill, whatever the toxicity to the patient.
Chronic Myelogenous Leukemia: Disease Biology and Current and Future Therapeutic Strategies
Authors: Kantarjian Hagop , Melo Junia V. , Tura Sante , Giralt Sergio , Talpaz Moshe 
Published: October 2019

Over the last 2 decades, four major therapeutic approaches have drastically changed the prognosis in chronic myelogenous leukemia (CML): 1) allogeneic stem cell transplant (SCT); 2) interferon alpha (IFN-α) based regimens; 3) donor lymphocyte infusions (DLI); and 4) and the revolutionary BCR-ABL tyrosine kinase inhibitors such as STI571 (signal transduction inhibitor 571). Each modality has exploited and targeted different aspects of CML biology, and is associated with different risk-benefit ratios.In Section I of this review, Dr. Melo reviews the molecular pathophysiology of CML and potential new targets for therapy including anti-sense strategies to disrupt the BCR-ABL gene and inhibition of the BCR-ABL tyrosine kinase activity.In Section II, Dr. Tura, addresses important questions in the use of IFN-α for the treatment of CML, including the mechanism of action and the development of resistance, the optimal dose and duration of therapy and the prediction of response based on clinical features. An approach to the choice of therapy based on the predicted mortality is presented.In Section III Dr. Giralt presents an update on the results of unrelated donor transplantion, donor lymphocyte infusions (DLI) and non-ablative stem cell transplantation (NST) in CML. The roles of CD8-depletion, dose escalation and the transduction of suicide genes in treatment with DLI are addressed. Early results of NST in CML show that it is feasible and can result in long-term disease control.In Section IV Drs. Kantarjian and Talpaz review the results of IFN-α plus low-dose cytosine arabinoside and other promising modalities for CML including homoharringtonine, decitabine, and polyethylene glycol-interferon. In Section V they present an update on the recent experience with STI571. Objective but transient responses have been seen in 40% to 50% of patients in CML blastic phase. In accelerated phase, the response rate with STI571 exceeds 70%, and these responses are durable. In chronic phase CML, STI571 at 300 mg daily in patients who failed IFN-α produces a complete hematologic response (CHR) in over 90% of patients. Early results suggest cytogenetic response rates of approximately 50%, which may be major in approximately 30%. The maturing results with STI571 may soon change current recommendations regarding the relative roles of established modalities such as allogeneic SCT and IFN-α. Important questions include 1) whether STI571 therapy alone may be sufficient to induce long-term survival and event-free survival in CML, or whether it needs to be combined simultaneously or sequentially with IFN-α and cytosine arabinoside; and 2) what should the indications for frontline allogeneic SCT be in relation to STI571 therapy.
Thrombophilia: What's a Practitioner to Do?
Authors: Macik B. Gail , Rand Jacob H. , Konkle Barbara A. 
Published: October 2019

Abstract
Management of thrombophilia is an ever-changing field as new disorders are described and additional clinical experience accrues. This paper addresses three common management issues in the care of patients with thrombophilia. The first two topics are updates for common but perplexing hypercoagulable states and the last topic introduces a new option for optimal management of oral anticoagulant therapy. Dr. Jacob Rand updates and organizes the approach to patients with antiphospholipid syndrome. This syndrome is a common acquired thrombophilic state, but the diagnosis and treatment of patients remains a challenge. Dr. Rand outlines his diagnostic and treatment strategies based on the current understanding of this complicated syndrome. Dr. Barbara Konkle addresses the special concerns of managing women with thrombophilia. Hematologists are often asked to advise on the risks of hormonal therapy or pregnancy in a woman with a personal or family history of thrombosis or with an abnormal laboratory finding. Dr. Konkle reviews the available data on the risks of hormonal therapy and pregnancy in women with and without known underlying thrombophilic risk factors. In Section III, Dr. Gail Macik will discuss a new approach to warfarin management. Several instruments are now available for home prothrombin time (PT) monitoring. Self-testing and self management of warfarin are slowly emerging as reliable alternatives to traditional provider-based care and Dr. Macik reviews the instruments available and the results of studies that support this new management option.
Costs of Care in Hemophilia and Possible Implications of Health Care Reform
Authors: Johnson Kathleen A. , Zhou Zheng-Yi 
Published: October 2019

AbstractEconomic evaluation in health care is increasingly used to assist policy makers in their difficult task of allocating limited resources. The high cost of care, including that for clotting factor concentrates, makes hemophilia a potential target for cost-cutting efforts by health care payers. Although the appropriate management of hemophilia is key to minimizing and preventing long-term morbidity, comparative effectiveness studies regarding the relative benefit of different treatment options are lacking. Cost-of-illness (COI) analysis, which includes direct and indirect costs from a societal perspective, can provide information to be used in cost-effectiveness and other economic analyses. Quality-of-life assessment provides another methodology with which to measure outcomes and benefits of appropriate disease management. Health care reform has implications for individuals with hemophilia and their families through changes in payment, insurance coverage expansion, and health care delivery system changes that reward quality and stimulate cooperative, team-based care. Providers will benefit from the expansion of insurance coverage and some financial benefits in rural areas, and from the expansion of coverage for preventive services. Accountable care organizations will potentially change the way providers are paid and financial incentives under reform will reward high quality of care.
Where do we stand in the treatment of relapsed acute lymphoblastic leukemia?
Authors: Raetz Elizabeth A. , Bhatla Teena 
Published: October 2019

Abstract
Acute lymphoblastic leukemia (ALL) is the most common and one of the most treatable cancers in children. Although the majority of children with ALL are now cured, 10%-20% of patients are predicted to relapse and outcomes with salvage therapy have been disappointing, with approximately only one-third of children surviving long-term after disease recurrence. Several prognostic factors have been identified, with timing of recurrence relative to diagnosis and site of relapse emerging as the most important variables. Despite heterogeneity in the elements of salvage therapy that are delivered in trials conducted internationally, outcomes have been remarkably similar and have remained static. Because most intensive salvage regimens have reached the limit of tolerability, current strategies are focusing on identifying new agents tailored to the unique biology of relapsed disease and identifying methods to develop these agents efficiently for clinical use. Recently, high-resolution genomic analyses of matched pairs of diagnostic and relapse bone marrow samples are emerging as a promising tool for identifying pathways that impart chemoresistance.
Minimal residual disease: optimal methods, timing, and clinical relevance for an individual patient
Authors: Schrappe Martin 
Published: October 2019

Abstract
After approximately 20 years of development and after several prospective clinical trials, the detection of minimal residual disease (MRD) has emerged as part of state-of-the-art diagnostics to guide the majority of contemporary treatment programs both in pediatric and adult acute lymphoblastic leukemia (ALL). For ALL, several methods of MRD analysis are available, but 2 are widely applicable. One is based on the detection of aberrant expression of leukemia specific antigens by flow cytometry and the other one uses the specific rearrangements of the TCR or Ig genes, which can be detected by quantitative PCR in the DNA of leukemic cells. In some cases with known fusion genes such as BCR/ABL, RT-PCR can be used as a third method of identifying leukemic cells by analyzing RNA in patient samples. Clinical application of such sophisticated tools in the stratification and treatment of ALL requires reliable, reproducible, and quality-assured methods to ensure patient safety.
Matched and mismatched unrelated donor transplantation: is the outcome the same as for matched sibling donor transplantation?
Authors: Bacigalupo Andrea 
Published: October 2019

Abstract
The outcome of allogeneic stem cell transplantation has improved over the past decades due to a significant reduction of nonrelapse mortality, whereas our ability to control underlying malignant diseases has remained unchanged. Reduction of nonrelapse mortality has been achieved in matched sibling donor transplantation, but perhaps more so with unrelated donor transplantation, in part due to the advances in HLA matching between donor and recipient, but also as a result of improved supportive care, better GVHD prophylaxis, and tailored conditioning regimens. Therefore, over the past decade, results of matched sibling donor and unrelated donor grafts have grown more similar, and the difference in 1-year survival for patients with leukemia has gone from 21% in 1988 in favor of MSD to 9% in 2008. However, due to the significant and combined effect of patient, transplantation, and donor variables, comparisons are made here in the context of defined subsets of patients and specific diseases and in some circumstances also looking at separate studies in children and adults.
Health-related quality of life in patients with hemoglobinopathies
Authors: Panepinto Julie A. 
Published: October 2019

Abstract
The use of patient-reported outcomes to measure the health and well-being of patients from their perspective has become an acceptable method to determine the impact of a disease and its treatment on patients. In patients with hemoglobinopathies, prior work has demonstrated that patients experience significant impairment in health-related quality of life (HRQL, a type of patient-reported outcome). This work has provided a better understanding of the burden that these patients experience and the factors that are associated with worse HRQL. The recent development of disease-specific HRQL instruments in sickle cell disease heralds new opportunities to explore the impact of the disease and its treatment on patients. The standards necessary to incorporate the measurement of HRQL into clinical trials are now well outlined by regulatory agencies. Measuring HRQL within a clinical practice setting and outside of the healthcare setting while the patient is at home are now possible and present new opportunities to understand the health and well-being of patients with hemoglobinopathies.
What is the evidence that hydroxyurea improves health-related quality of life in patients with sickle cell disease?
Authors: Darbari Deepika S. , Panepinto Julie A. 
Published: October 2019

Abstract
A 10-year-old male patient with homozygous sickle cell disease presents for a follow-up clinic visit after a recent hospitalization for a painful vasoocclusive event. His parents mention that in the past year he has had 4 hospitalizations for vasoocclusive events, 2 of which were complicated by the development of acute chest syndrome that resulted in transfer to the intensive care unit. He has missed many school days and may be retained a grade this year. He feels particularly sad about missing the school field trip that occurred during his last hospitalization. He also reports that he is not able to keep up with his friends when participating in physical activities at school. The child's parents are worried that he may be depressed. You as the provider discuss the option of hydroxyurea therapy. His parents ask if hydroxyurea would improve his overall well-being and functioning.
How does PET/CT help in selecting therapy for patients with Hodgkin lymphoma?
Authors: Hutchings Martin 
Published: October 2019

Abstract
Positron emission tomography/computed tomography (PET/CT) has emerged as the most accurate tool for staging, treatment monitoring, and response evaluation in Hodgkin lymphoma (HL). Accurate staging and restaging are very important for the optimal management of HL, but we are only beginning to understand how to use PET/CT to improve treatment outcome. More precise determination of disease extent may result in more precise pretreatment risk stratification, and is also essential for the minimal and highly individualized radiotherapy volumes of the present era. Several trials are currently investigating the use of PET/CT for early response-adapted therapy, with therapeutic stratification based on interim PET/CT results. Posttreatment PET/CT is a cornerstone of the revised response criteria and enables the selection of advanced-stage patients without the need for consolidation radiotherapy. Once remission is achieved after first-line therapy, PET/CT seems to have little or no role in the routine surveillance of HL patients. PET/CT looks promising for the selection of therapy in relapsed and refractory disease, but its role in this setting is still unclear.
Minimal residual disease in acute myeloid leukemia: coming of age
Authors: Paietta Elisabeth 
Published: October 2019

Abstract
The achievement of complete hematologic remission (CR) is a prerequisite for cure in acute myeloid leukemia (AML). The conventional definition of CR, based on the morphologic recognition of ≤ 5% of leukemic blasts in the BM, does not provide sufficient insight into the quality of the response. Despite CR rates of 50%-80% (depending on age), the majority of patients with AML relapse within 3-5 years from diagnosis. Therefore, there is great need of more sensitive prognostic factors that can predict relapse. Minimal residual disease (MRD), defined as any measurable disease or leukemia detectable above a certain threshold (defined by the methodology applied), predicts failure to maintain a morphologic CR and affects survival negatively. AML is lagging behind acute lymphoblastic leukemia with respect to the implementation of MRD criteria for guidance during therapy. AML is particularly disadvantaged compared with acute lymphoblastic leukemia in that approximately half of AML patients lack a molecular target suitable for MRD monitoring. The detection of altered antigen (Ag) expression by leukemic myeloblasts is a valid alternative to DNA- or RNA-based MRD assays. Although associated with presenting prognostic factors (eg, cytogenetics and genotype), MRD represents the collective end result of all of the cellular mechanisms that determine a patient's response to a given therapy. Therefore, MRD has 2 potential roles in AML treatment: (1) as a posttherapy prognosticator used to assign patients to optimal postinduction/consolidation therapy, and (2) as an early surrogate end point for the evaluation of therapy efficacy.
Doublets, triplets, or quadruplets of novel agents in newly diagnosed myeloma?
Authors: Rajkumar S. Vincent 
Published: October 2019

Abstract
The treatment of multiple myeloma is evolving rapidly. A plethora of doublet, triplet, and quadruplet combinations have been studied for the treatment of newly diagnosed myeloma. Although randomized trials have been conducted comparing older regimens such as melphalan-prednisone with newer regimens containing drugs such as thalidomide, lenalidomide, or bortezomib, there are few if any randomized trials that have compared modern combinations with each other. Even in the few trials that have done so, definitive overall survival or patient-reported quality-of-life differences have not been demonstrated. Therefore, there is marked heterogeneity in how newly diagnosed patients with myeloma are treated around the world. The choice of initial therapy is often dictated by availability of drugs, age and comorbidities of the patient, and assessment of prognosis and disease aggressiveness. This chapter reviews the current data on the most commonly used and tested doublet, triplet, and quadruplet combinations for the treatment of newly diagnosed myeloma and provides guidance on choosing the optimal initial treatment regimen.
When, how, and what cell source for hematopoietic cell transplantation in first complete remission adult acute lymphoblastic leukemia?
Authors: Lazarus Hillard M. , Advani Anjali S. 
Published: October 2019

AbstractAdult acute lymphoblastic leukemia (ALL) is a heterogeneous disease affected by many patient- and disease-related factors, including age, immunologic subtype, and clinical, genetic, and molecular features. Allogeneic hematopoietic cell transplantation (HCT) has occupied an increasing therapeutic role as a result of significant improvements in supportive care and histocompatibility testing. ALL Philadelphia chromosome–negative patients formerly excluded now are considered HCT candidates and survival rates with alternative donors may approach those obtained with matched-related donors. Reduced-intensity conditioning rather than myeloablative conditioning appears to provide comparable patient outcome results although these observations have not been validated in prospective studies. Improved tools can identify patients thought to be in remission based on morphology but who have active disease at the molecular or immunophenotypic level (minimal residual disease). Using B-cell antigen panels, clone-specific immunoglobulins, or T-cell receptor rearrangements to detect positivity at thresholds of at least 1 in 104 cells, such patients may be taken to HCT. The ongoing advances in conventional therapy intensity, however, now yield improved results and ongoing reassessment of the place of HCT needs to be continued; every effort should be made to enroll eligible patients in clinical trials.