bluuebunny/crossref_metadata_2025_split huggingface dataset:
Current treatment algorithm for the management of patients with myelofibrosis, JAK inhibitors, and beyond
Authors: Harrison Claire N. , McLornan Donal P. 
Published: April 2019

Abstract
Myelofibrosis (MF) is a heterogeneous disorder characterized by splenomegaly, constitutional symptoms, ineffective hematopoiesis, and an inherent risk of leukemic transformation. The past decade has seen a massive shift in available therapeutic options for our patients and we are learning how and when to use novel agents, either alone or in combination, during the disease course. This has translated into improved management of splenomegaly, significant amelioration in disease-related symptom burden for many, and may lead to improved survival. But limitations in the therapeutic options remain. Moreover, enhanced delineation of the mutational landscape of MF has offered both increasingly complex prognostic algorithms and yielded further potential therapeutic avenues. In this review, we will focus on stratifying both standard and experimental therapeutic management in 2017 and 2018 and postulate on the emerging treatments that will likely become part of our increasingly complex treatment algorithm.
Secondary CNS relapse in diffuse large B-cell lymphoma: defining high-risk patients and optimization of prophylaxis strategies
Authors: Savage Kerry J. 
Published: April 2019

Abstract
Despite improvement in survival in diffuse large B-cell lymphoma (DLBCL) with the introduction of rituximab, central nervous system (CNS) relapse continues to represent a clinical challenge. A number of studies have evaluated clinical risk factors in an attempt to identify high-risk patients to direct CNS staging investigations and consider prophylaxis strategies. The CNS International Prognostic Index is a robust and reproducible risk model that can identity patients at high risk of CNS relapse, but its specificity remains limited. Studies are emerging of biomarkers that predict CNS relapse that can be integrated with clinical risk models to better identify high-risk patients for CNS-directed prophylaxis strategies. Because CNS parenchymal disease is the predominant compartment, prophylaxis should include deeply penetrant drugs such as high-dose methotrexate. However, this has been associated with toxicity and has limited use in older patients. Novel therapies are being tested in primary CNS lymphoma with encouraging results and may represent rational strategies to be further explored in the prophylaxis setting.
Treatment of inherited bone marrow failure syndromes beyond transplantation
Authors: Calado Rodrigo T. , Clé Diego V. 
Published: April 2019

AbstractDespite significant progress in transplantation by the addition of alternative hematopoietic stem cell sources, many patients with inherited bone marrow failure syndromes are still not eligible for a transplant. In addition, the availability of sequencing panels has significantly improved diagnosis by identifying cryptic inherited cases. Androgens are the main nontransplant therapy for bone marrow failure in dyskeratosis congenita and Fanconi anemia, reaching responses in up to 80% of cases. Danazol and oxymetholone are more commonly used, but virilization and liver toxicity are major adverse events. Diamond-Blackfan anemia is commonly treated with corticosteroids, but most patients eventually become refractory to this treatment and toxicity is limiting. Growth factors still have a role in inherited cases, especially granulocyte colony-stimulating factor in congenital neutropenias. Novel therapies are warranted and thrombopoietin receptor agonists, leucine, quercetin, and novel gene therapy approaches may benefit inherited cases in the future.
The new tool “KIT” in advanced systemic mastocytosis
Authors: Shomali William , Gotlib Jason 
Published: April 2019

AbstractMastocytosis is a rare disease characterized by KIT-driven expansion and accumulation of neoplastic mast cells in various tissues. Although mediator symptoms related to mast cell activation can impose a symptom burden in cutaneous disease and across the spectrum of systemic mastocytosis subtypes, the presence of an associated hematologic neoplasm and/or organ damage denotes advanced disease and the potential for increased morbidity and mortality. In addition to the revised 2016 World Health Organization classification of mastocytosis, a new diagnostic and treatment toolkit, tethered to enhanced molecular characterization and monitoring, is poised to transform the management of patients with advanced systemic mastocytosis (advSM). Although the efficacy of midostaurin and novel selective KIT D816V inhibitors, such as avapritinib (BLU-285), have validated KIT as a therapeutic target, the clinical and biologic heterogeneity of advSM requires that we reimagine the blueprint for tackling these diseases and use tools that move beyond KIT-centric approaches.
Are CAR T cells better than antibody or HCT therapy in B-ALL?
Authors: Pulsipher Michael A. 
Published: April 2019

Abstract
Multicenter trials in children and young adults using second-generation CD19-targeted chimeric antigen receptor (CAR) T cells have shown dramatic levels of remission in patients with multiply relapsed/refractory disease (80% to ≥90%). Early results in adult trials have also shown significant responses, and strategies aimed at mitigating toxicities associated with the therapy have improved tolerability. Therefore, if available, CAR T-cell therapy deserves consideration for salvage of children and adults with B-lineage acute lymphoblastic leukemia (B-ALL) who are multiply relapsed, refractory, or relapsed after a previous allogeneic transplantation. For patients with a first relapse or who have persistent minimal residual disease (MRD) after initial or relapse therapy, treatment with blinatumomab or inotuzumab is reasonable to help patients achieve MRD− remission before definitive therapy with allogeneic hematopoietic cell transplantation (HCT). A number of studies in younger patients using 4-1BB–based CAR T-cell constructs lentivirally transduced into patient T cells and then optimally expanded have resulted in long-term persistence without further therapy. In 1 study using CD28-based CARs in adults, the benefit of HCT after CAR T-cell therapy was not clear, because a group of patients experienced long-term remissions without HCT. These data suggest that CAR T-cell therapy may be able to substitute for transplantation in many patients, avoiding the risks and long-term consequences of HCT. With this is mind, and with emerging data better defining ways of enhancing CAR T-cell persistence and avoiding relapse through antigen escape, CAR T cells will have a growing role in treatment of both pediatric and adult B-ALLs in the coming years.
Clinical consequences of clonal hematopoiesis of indeterminate potential
Authors: Steensma David P. 
Published: April 2019

Abstract
Clonally restricted hematopoiesis is a common aging-associated biological state that predisposes to subsequent development of a hematological malignancy or cardiovascular death. Clonal expansion driven by leukemia-associated somatic mutations, such as DNMT3A, ASXL1, or TET2, is best characterized, but oligoclonality can also emerge without recognized leukemia-driver mutations, perhaps as a result of stochastic neutral drift. Murine models provide compelling evidence that a major mechanism of increased cardiovascular mortality in the context of clonal hematopoiesis is accelerated atherogenesis driven by inflammasome-mediated endothelial injury, resulting from proinflammatory interactions between endothelium and macrophages derived from circulating clonal monocytes. Altered inflammation likely influences other biological processes as well. The rate of development of overt neoplasia in patients with clonal hematopoiesis of indeterminate potential (CHIP), as currently defined, is 0.5% to 1% per year. Contributing factors to clonal progression other than acquisition of secondary mutations in hematopoietic cells (ie, stronger leukemia drivers) are incompletely understood. Disordered endogenous immunity in the context of increased proliferative pressure, short telomeres leading to chromosomal instability, an unhealthy marrow microenvironment that favors expansion of clonal stem cells and acquisition of new mutations while failing to support healthy hematopoiesis, and aging-associated changes in hematopoietic stem cells, including altered DNA damage response, an altered transcriptional program, and consequences of epigenetic alterations, are all potential contributors to clonal progression. Clinical management of patients with CHIP includes monitoring for hematological changes and reduction of modifiable cardiovascular risk factors; eventually, it will also likely include anti-inflammatory therapies and targeted approaches to prune emergent dangerous clones.
The MDS genomics-prognosis symbiosis
Authors: Nazha Aziz 
Published: April 2019

Abstract
Myelodysplastic syndromes (MDS) are clonal disorders characterized by the accumulation of complex genomic abnormalities that define disease phenotype, prognosis, and the risk of transformation to acute myeloid leukemia. The clinical manifestations and overall outcomes of MDS are very heterogeneous with an overall survival that can be measured in years for some patients to a few months for others. Prognostic scoring systems are important staging tools that aid physicians in their treatment recommendations and decision-making and can help patients understand their disease trajectory and expectations. Several scoring systems have been developed in MDS with the International Prognostic Scoring System and its revised version, the most widely used systems in clinical practice and trial eligibility. These models and others use mainly clinical variables that are obtained from bone marrow biopsy and peripheral blood measurements. Adding molecular data to current models may improve its predictive power but the ultimate method to incorporate this information remains a work in progress. Novel methods to develop a personalized prediction model that provides outcomes that are specific for a patient are currently under way and may change how we think about risk stratification in MDS patients in the future.
The rheumatology/hematology interface: CAPS and MAS diagnosis and management
Authors: Gansner John M. , Berliner Nancy 
Published: April 2019

Abstract
Catastrophic antiphospholipid antibody syndrome (CAPS) and macrophage activation syndrome (MAS) are both life-threatening hematologic disorders that infrequently afflict patients with rheumatologic disease. CAPS is characterized by fulminant multiorgan damage related to small vessel thrombosis in the setting of persistent antiphospholipid antibodies. It can occur in patients with rheumatologic diseases such as systemic lupus erythematosus but can also affect patients who do not have rheumatologic disease. By contrast, the term MAS is applied when patients with rheumatologic disease develop hemophagocytic lymphohistiocytosis (HLH); therefore, patients with MAS have an underlying rheumatologic disease by definition. Similar to CAPS, HLH/MAS can have a fulminant presentation, but the pathogenesis and manifestations are different. In both CAPS and MAS, management generally includes but is not limited to immunosuppression with steroids. Fatalities are relatively common and morbidity is often significant. Early recognition of these disorders and initiation of timely treatment are important. More effective therapies for both syndromes are urgently needed.
Novel insights and therapeutic approaches in idiopathic multicentric Castleman disease
Authors: Fajgenbaum David C. 
Published: April 2019

Abstract
Castleman disease (CD) describes a heterogeneous group of hematologic disorders that share characteristic lymph node histopathology. Patients of all ages present with either a solitary enlarged lymph node (unicentric CD) or multicentric lymphadenopathy (MCD) with systemic inflammation, cytopenias, and life-threatening multiple organ dysfunction resulting from a cytokine storm often driven by interleukin 6 (IL-6). Uncontrolled human herpesvirus-8 (HHV-8) infection causes approximately 50% of MCD cases, whereas the etiology is unknown in the remaining HHV-8-negative/idiopathic MCD cases (iMCD). The limited understanding of etiology, cell types, and signaling pathways involved in iMCD has slowed development of treatments and contributed to historically poor patient outcomes. Here, recent progress for diagnosing iMCD, characterizing etio-pathogenesis, and advancing treatments are reviewed. Several clinicopathological analyses provided the evidence base for the first-ever diagnostic criteria and revealed distinct clinical subtypes: thrombocytopenia, anasarca, fever, reticulin fibrosis/renal dysfunction, organomegaly (iMCD-TAFRO) or iMCD-not otherwise specified (iMCD-NOS), which are both observed all over the world. In 2014, the anti-IL-6 therapy siltuximab became the first iMCD treatment approved by the US Food and Drug Administration, on the basis of a 34% durable response rate; consensus guidelines recommend it as front-line therapy. Recent cytokine and proteomic profiling has revealed normal IL-6 levels in many patients with iMCD and potential alternative driver cytokines. Candidate novel genomic alterations, dysregulated cell types, and signaling pathways have also been identified as candidate therapeutic targets. RNA sequencing for viral transcripts did not reveal novel viruses, HHV-8, or other viruses pathologically associated with iMCD. Despite progress, iMCD remains poorly understood. Further efforts to elucidate etiology, pathogenesis, and treatment approaches, particularly for siltuximab-refractory patients, are needed.
Anticoagulating patients with high-risk acquired thrombophilias
Authors: Skeith Leslie 
Published: April 2019

Abstract
Antiphospholipid syndrome (APS), heparin-induced thrombocytopenia, and paroxysmal nocturnal hemoglobinuria are 3 acquired thrombophilias that carry a high risk of venous and arterial thromboembolism. Management of these conditions has largely included anticoagulation with a vitamin K antagonist after an initial period of a parenteral anticoagulant, for as long as the thrombotic risk is still present. The available evidence for the use of direct oral anticoagulants (DOACs) is limited and primarily consists of case series and cohort studies, which are summarized in this chapter. Randomized trials evaluating DOACs in patients with APS are reviewed. Further research is needed prior to widely adopting DOACs for use in these high-risk acquired thrombophilias; however, there may be selected low-risk subgroups where DOAC use is possible after careful consideration and patient discussion.
Approach to the treatment of the older, unfit patient with myeloma from diagnosis to relapse: perspectives of a US hematologist and a geriatric hematologist
Authors: Wildes Tanya M. , Anderson Kenneth C. 
Published: April 2019

Abstract
Mrs. A. is a 73-year-old woman who has developed increasing fatigue and lower back pain over the past year. The pain limits her exercise tolerance such that she can now walk only 1 block. She is a retired schoolteacher who does volunteer efforts in her community but has limited her activities due to fatigue. Karnofsky performance status is 70%. She has a history of chronic hypertension treated with a diuretic, adult-onset diabetes mellitus treated with metformin, and hypothyroidism treated with levothyroxine. Initial evaluation reveals anemia, renal dysfunction, an elevated total protein, and an L2 compression fracture on lumbosacral radiographs. Results of initial and subsequent evaluation are shown below, and she is referred to a hematologist for further evaluation, which revealed the following: calcium 9.0 mg/dL, creatinine 3.2 mg/dL with estimated creatinine clearance using the Modification of Diet in Renal Disease equation of 15 mL/min, hemoglobin 9.6 g/dL, total protein 11 g/dL, albumin 3.2 g/dL, immunoglobulin A (IgA) λ M protein 6.8 g/dL, total IgA 7.2 g/dL, IgG 0.4g/dL, IgM 0.03 g/dL, free κ <0.01 mg/L, free λ 1000 mg/L, serum free light chain ratio <0.01, β-2–microglobulin 4.2, viscosity 3.0, lactate dehydrogenase 200 U/L, urine protein electrophoresis: 125 mg/dL with 30% M protein, and urine immunofixation: λ light chain. Skeletal bone survey showed lytic lesions in femurs and humeri and diffusely in ribs bilaterally as well as compression fractures at T4, T6, and L2. Bone marrow biopsy revealed λ-restricted plasma cells comprising 50% of the bone marrow core. Fluorescence in situ hybridization testing on marrow showed that del 17p was present in 80% of the plasma cells. Mrs. A. is informed of the diagnosis of multiple myeloma and the need for therapy. She requests consultation with 2 of the leading world experts. However, she wants to be treated near her home and does not want treatment on a clinical trial.
Adipocyte alterations in endometriosis: reduced numbers of stem cells and microRNA induced alterations in adipocyte metabolic gene expression
Authors: Zolbin Masoumeh Majidi , Mamillapalli Ramanaiah , Nematian Sepide E. , Goetz Teddy G. , Taylor Hugh S. 
Published: April 2019

Abstract
Background
Endometriosis is an estrogen dependent, inflammatory disorder occurring in 5–10% of reproductive-aged women. Women with endometriosis have a lower body mass index (BMI) and decreased body fat compared to those without the disease, yet few studies have focused on the metabolic abnormalities in adipose tissue in women with endometriosis. Previously, we identified microRNAs that are differentially expressed in endometriosis and altered in the serum of women with the disease. Here we explore the effect of endometriosis on fat tissue and identified a role for endometriosis-related microRNAs in fat metabolism and a reduction in adipocyte stem cell number.

Methods
Primary adipocyte cells cultured from 20 patients with and without endometriosis were transfected with mimics and inhibitors of microRNAs 342-3p or Let 7b-5p to model the status of these microRNAs in endometriosis. RNA was extracted for gene expression analysis by qRT-PCR. PCNA expression was used as a marker of adipocyte proliferation. Endometriosis was induced experimentally in 9-week old female C57BL/6 mice and after 10 months fat tissue was harvested from both the subcutaneous (inguinal) and visceral (mesenteric) tissue. Adipose-derived mesenchymal stem cells in fat tissue were characterized in both endometriosis and non-endometriosis mice by FACS analysis.

Results
Gene expression analysis showed that endometriosis altered the expression of Cebpa, Cebpb, Ppar-γ, leptin, adiponectin, IL-6, and HSL, which are involved in driving brown adipocyte differentiation, appetite, insulin sensitivity and fat metabolism. Each gene was regulated by an alteration in microRNA expression known to occur in endometriosis. Analysis of the stem cell content of adipose tissue in a mouse model of endometriosis demonstrated a reduced number of adipocyte stem cells.

Conclusions
We demonstrate that microRNAs Let-7b and miR-342-3p affected metabolic gene expression significantly in adipocytes of women with endometriosis. Similarly, there is a reduction in the adipose stem cell population in a mouse model of endometriosis. Taken together these data suggest that endometriosis alters BMI in part through an effect on adipocytes and fat metabolism.
Treat and extend regimen with aflibercept for chronic central retinal vein occlusions: 2 year results of the NEWTON study
Authors: Khurana Rahul N. , Chang Louis K. , Bansal Alok S. , Palmer James D. , Wu Chengqing , Wieland Mark R. 
Published: April 2019

Abstract
Background
To determine whether aflibercept (Eylea; Regeneron Pharmaceuticals, Inc., Tarrytown, NY) could continue to extend the macular edema free interval in patients on a treat and extend (TAE) with non-ischemic central retinal vein occlusions (CRVOs) previously treated with ranibizumab (Lucentis; Genentech, Inc., South San Francisco, CA) or bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA) in the second year.

Methods
Twenty patients with macular edema secondary to non-ischemic CRVOs previously treated with ranibizumab or bevacizumab were prospectively treated with intravitreal aflibercept injection (IAI) using a TAE dosing regimen. Injection frequencies were extended 2 weeks if there were no signs of disease activity on OCT or change in visual acuity. In the second year of the study, patients who have recurrences of macular edema could be re-challenged with a longer treatment interval under the following criterion: absence of any macular edema on three consecutive visits with the same treatment interval.

Results
Twenty patients had an average duration of a CRVO for 22 months (range 7–90) and averaged an anti-VEGF treatment every 42 days (range 28–60 days). The macular edema free interval increased from 38 to 75 days when switched to aflibercept (p = 0.000003) at month 24. There was an average increase of 37 days (median 34 days; range 0–91 days) in the macular edema free interval with aflibercept. At the month 24 visit, 50% (8/16) went > 12 weeks with a macular edema free interval between IAI. There was an improvement in vision (+ 8 ETDRS letters, p = 0.006) and decreased retinal thickness (158 µm, p = 0.00003) with aflibercept treatment at month 24.

Conclusions
The 2-year results of the NEWTON study demonstrated the sustained benefits of a TAE dosing regimen with aflibercept in patients with chronic CRVOs. The visual acuity gains and anatomic improvements observed at year one were maintained through month 24 with less visits and treatments. This may help minimize the treatment burden in patients with recurrent macular edema secondary to non-ischemic CRVO.
Trial Registration ClinicalTrials.gov, NCT01870427, Registered June 6, 2013, https://clinicaltrials.gov/ct2/show/NCT01870427?cond=NEWTON&rank=1.
Presented at the RETICON 2017: The Retina Congress with Live Surgery, Chennai, India-April 2017.