bluuebunny/crossref_metadata_2025_split huggingface dataset:
Real-World Clinical Experience with Long-Term Miglustat Therapy in Type 1 Gaucher Disease: The ZAGAL Project
Authors: Giraldo Pilar , Alfonso Pilar , Fernandez-Galan MAngeles , Martín-Nuñez Guillermo , Barez Abelardo , Franco Rafael , Alonso Dora , Acedo Antonio , Martin Alejandro , Martinez-Estefano Elvira , Roldan Vanessa , Serrano Sol , Latre Paz , Pocovi Miguel 
Published: April 2020

Abstract
Background and objectives: Several reports describe the use of miglustat (Zavesca®), an oral inhibitor of glucosylceramide synthase, for type 1 Gaucher disease (GD1) in clinical trials. There are few data on the use of miglustat for GD1 in the real-world clinical experience. Here, we assess the long-term efficacy, tolerability and safety of miglustat in a prospective, open-label, observational study of GD1 patients attending routine clinic visits.
Design and Methods: 48 patients with mild-to-moderate GD1 received miglustat 100 mg t.i.d. over 36 months. Patients were analysed in two groups: therapy-naïve patients (n = 11) and those switched from previous treatment with enzyme replacement therapy (ERT; n = 37). Assessments of clinical status, haematological parameters, and organomegaly were performed before treatment and after 6, 12, 24 and 36 months of therapy. Data were compared with a historical reference cohort 29 GD1 patients treated for 36 months with ERT.
Results: Nine treatment-naïve patients completed 36 months of miglustat therapy. Sustained improvements in haemoglobin were seen in all patients who had anaemia before treatment. Platelet counts improved in patients with initial thrombocytopenia, and were maintained in patients with normal counts at baseline. Plasma chitotriosidase activity decreased in treatment-naïve patients during the first year on therapy and remained stable thereafter. S-MRI findings indicated improved bone status at 36 months. In patients switched from ERT, 15 completed 36 months of miglustat therapy, and displayed maintained or improved clinical and haematological parameters, and surrogate disease severity markers. No statistically significant differences were observed at 36 months between treatmentnaïve patients with similar baseline characteristics treated with either miglustat or ERT. Overall, miglustat was well tolerated.
Interpretation and conclusions: Miglustat provided appreciable therapeutic responses on clinical, haematological, biomarker and S-MRI parameters at 36 months in patients with GD1, and was well tolerated. Therapeutic responses with miglustat were comparable with those seen with ERT.
Primary Extranodal Lymphoma: Revised Incidence, Location, Histological Classification and Survival in Zaragoza (Spain), 1992–2002
Authors: Giraldo Pilar , Franco-Garcia Esther , Alvarez Ramiro , Garcia-Carpintero Gloria , Pascual Mercedes , Martos Carmen 
Published: April 2020

Abstract
Background. Leukaemia and non-Hodgkin’s lymphomas (NHL) are the commonest haematological malignancies (HMs), accounting for about 10% of incident cases and 6% of all cancer deaths in the European Union (EU). There are few studies in order to estimate the differences in incidence and survival of primary extranodal Lymphoma (PEL). In Zaragoza (Spain) there is a population-based Cancer Registry (ZPCR), that includes all non-haematological and haematological (HMs) incident cases, conducted since 1960. The main aims of this study are:
To review all cases with PEL diagnosis. To estimate the incidence of PEL in the ZPCR registered cases during the period 1992–2002. 2. To calculate the survival of PEL
Methods. All PEL occurred in patients residing in Zaragoza during the period 1992–2002 were selected from ZPCR. All cases were reviewed in order to confirm the primary location and the morphology classification according to REAL. The population at risk was 9.266.609 person-years. The crude (CIR) and age standardized incidence rate (ASR) were calculated, using the European population as standard. Kaplan-Maier method was applied to calculate median survival time and their 95% confidence intervals, as well as 5-year survival. The end of follow-up was 31 December 2007 and Log-Rank was used to compare survival curves.
Results. Among all 4,340 HMs, a total of 1,757 (40.0%) were NHL (CIR: 19×105 person-year), 252 (14.0%) of them were classified as PEL, yielding an ASR of 2.1×105 person-year (males: 140 cases (53.0%), mean age: 59.2 years, ASR: 2.7×105 person-year and females 112 cases (47.0%), mean age: 66.8 years ASR: 1.6×105 person-year. According to topography the most frequent sites were digestive tract (50.4%), skin (19.8%), gland tissue (10.0%), oral cavity-pharynx (7.9%), lung (2.9%), CNS (2.4%), orbit (2.1%) and others (4.5%). The median survival for PEL was 6.61 years (95%CI: 3.7–9.5) and for nodal Lymphomas 5.01 years (95%CI: 4.1–5.9). The 5-year relative survival was 53.5% and 50.0% respectively. There are not significant differences between both groups. Moreover, non significant differences in survival were observed between males and females. Theses results are similar to those found in the EU.
Conclusions. The occurrence of PEL according to gender and mean age is similar to nodal NHL. No significant differences in survival were observed between nodal and extranodal NHL, probably the survival is more conditioned by the histology than topography.
A Systematic Review of the Cost-Effectiveness of Recombinant Factor VIIa (rFVIIa) and Activated Prothrombin Complex Concentrate (aPCC) in the Treatment of Mild to Moderate Bleeding Episodes for Haemophilia Patients with Inhibitors
Authors: Knight Chris , Danø Anne Møller , Kennedy-Martin Tessa 
Published: April 2020

Abstract
Objectives: Although haemophilia patients with inhibitors are rare, the clinical, humanistic and economic consequences associated with this disorder are considerable. The primary treatment for such patients is either rFVIIa or aPCC. The aim of this study was to identify, review and evaluate the quality of the published literature on the relative cost-effectiveness of rFVIIa and aPCC in treating haemophilia patients with inhibitors.
Methods: The review concentrates on the model type, the model design, model assumptions, and results.
Results: The results of this study suggest that rFVIIa may be the cost-effective alternative to treatment with aPCC due to the superior efficacy of rFVIIa and hence the avoidance of subsequent lines of treatment. In 7 of the 9 studies, rFVIIa had the lower average treatment cost. The adapted modelling framework is similar in all the economic models reviewed, suggesting clinical acceptability of the approach used. The estimates of efficacy varied between the models, especially for aPCC. The efficacy for aPCC derived from retrospective studies was lower than reported in the literature. Sensitivity analysis had been undertaken in the majority of the economic analyses and the results were found to be robust to realistic parameter variations. Only one of the studies was a cost-utility study, showing the lack of measuring health status within this area. The results showed the large impact appropriate treatment can have on the quality of life for haemophilia patients with inhibitors.
Conclusions: Ideally, there should be a systematic approach to identifying the relevant data and the lack of data from relevant randomized head-to-head trials is a contributing factor to the variation in efficacy rates and average dosages assumed. However, this systematic review has shown that despite differences in the estimates of efficacy, average dosage required, and unit costs the overall results are robust and appear to favour rFVIIa as the cost-effectiveness treatment for haemophilia patients with inhibitors.
Ambulatory Patient Preference for VTE Prophylaxis
Authors: Sousou Tarek , Khorana Alok 
Published: April 2020

Abstract
Introduction: Cancer-associated thrombosis leads to morbidity and mortality in cancer patients. Thromboembolism can be prevented with the use of existing and emerging anticoagulants. We sought to ascertain awareness as well as receptiveness to anticoagulation amongst ambulatory cancer patients receiving active therapy.
Methods: Two-hundred-fifty 12 question surveys were distributed to ambulatory cancer patients at the James P. Wilmot Cancer Center of the University of Rochester. Patients included in this study were those with active cancer, age ≥ 18 years and ambulatory. Hospitalized patients were excluded. Data was gathered regarding: age, gender, stage as well as type of malignancy, awareness of increased risk of venous thromboembolism and willingness to use various forms of anticoagulation.
Results: One hundred ninety surveys (76%) were completed over a three week period. Study population consisted of 71 males (37%) and 119 females (63%) with mean age of 58. Malignancies surveyed include: lymphoma 26%, breast 20%, gastrointestinal 15%, leukemia 9% and lung cancer 7% among others. Nineteen percent of patients had stage IV malignancy. Of the patients surveyed, 53% reported being unaware of the increased risk of VTE with malignancy. Eighty-six percent of patients surveyed would be willing to use an oral anticoagulant 46% would be willing to perform daily anticoagulant injections.
Conclusions: Prophylaxis for VTE in ambulatory cancer patients is an area of active investigation and could lead to improvements in morbidity and mortality. This study reveals a lack of knowledge of the increased risk of VTE amongst cancer patients. However, informed patients expressed willingness to use prophylaxis if shown effective to reduce VTE in the ambulatory setting.
Bone Marrow Specific Scatter Pattern on Multiple Myeloma and the M:E Ratio and Cellularity Analysed by the CELL-DYN 4000® Methodology
Authors: Simoes Ana Teresa , Barreira Rogerio FC , Pereira Alexandra Alves , Cardeira Sara , Sanches Raquel , Costa Carla Silva , Gonsalves Ana Paula , Marques Adilia , Santos Susana , Salvado Ramon , Duarte Marta , Ribeiro Maria Leticia 
Published: April 2020

Abstract
INTRODUCTION: Optical microscopy is the reference method for the morphological evaluation of bone marrow aspirates; however, in spite of permitting a good qualitative evaluation, the relative quantification of the different type of cells is time consuming and not precise. Regardless the efforts to develop automatic methodologies, no precise and reliable methods are available. CELL-DYN 4000® haematological analyzer uses the MAPSS® technology, based on optical light dispersion, fluorescence and impedance, with great accuracy in differential cellular blood counts.
STUDY PURPOSE:
to establish the correlation between the optical microscopy and the automatically CELL-DYN 4000® bone marrow examination concerning the cellularity and the myeloid/erythroid ratio. to study the bone marrow scatter pattern on haematological diseases.
MATERIAL AND METHODS: 84 bone marrow samples (in K3EDTA) collected for diagnostic purposes among patients attending the Haematology clinic of Centro Hospitalar de Coimbra. Bone marrow films were stained by May-Grünwald-Giemsa’s, analysed by two different Haematologists and the diagnosis were confirmed by flow cytometry studies. Bone marrow automatic analysis were performed by CELL-DYN 4000® using CBC(N), Extended Count(W) and Resistant(R) methodologies.
Statistical analysis: Pearson’s correlation for agreement between automatic methodologies for erythroid lineage and lymphoid series counts; Pearson’s correlation for M:E ratio; Cohen’s Kappa Test for the cellularity; Fisher’s Exact Test to determine whether a specific graphical pattern was associated with a particular haematological disease.
RESULTS: Comparing bone marrow studies by manual and automatic methods we verified:
a good correlation (r=0,769, p&lt;0,0001) with R methodology for erythroid lineage and lymphoid series, despite the interference of erythroblasts in the lymphoid series; an excellent agreement (k&gt;0,808) in the cellularity assessment and an excellent correlation (r=0,955; p&lt;0,0001) with the R methodology in M:E ratio.
We also found a very good association (c2=24; p&lt;0,0001) of a specific scatter pattern and Multiple Myeloma (n=10) which is different from Plasmocytic Leukaemia (n=2) and Monoclonal Gammopathy of Undetermined Significance (MGUS) (n=2).
CONCLUSIONS: The present study shows that the bone marrow M:E ratio, as well as the cellularity evaluation by CELL-DYN® 4000 R methodology are reliable. It also shows the association between a specific graphic pattern and Multiple Myeloma. Morphological analysis is the gold standard for bone marrow examination and it will be, probably, never discharged, however, these data confirm the possibilities of having a good global evaluation of bone marrow samples by automatic methods.
TG-Interacting Factor Regulates Proliferation and Differentiation of Human Myeloid Leukemia Cells
Authors: Hamid Rizwan , Brandt Stephen J. 
Published: April 2020

Abstract
Transforming growth-interacting factor (TGIF) is a homeobox transcriptional repressor that has been implicated in holoprosencephaly and various types of cancer. TGIF is expressed in hematopoietic stem cells and modulates TGF-β and retinoic acid (RA) signaling, both of which play an important role in hematopoiesis. We recently reported that TGIF’s levels correlate inversely with survival in patients with acute myelogenous leukemia. Here we present the first direct evidence of a role for TGIF in myelopoiesis. We used short hairpin RNA interference to define the effects of TGIF knockdown on proliferation and differentiation of myeloid leukemia-derived cell lines. We show that TGIF levels increase with myeloid differentiation and its knockdown resulted in reduced proliferation and differentiation, and lower expression of CEBPβ, CEBPε, PU.1 and RUNX1, key myeloid transcription factors. The reduction in proliferation was not attributable to a block at a particular stage of cell cycle or a significant increase in apoptosis. Furthermore, we show that TGIF knockdown results in increased TGF-β and decreased RA signaling. Consistent with our progenitor cell line results, bone marrow cells derived from Tgif-null mice produced reduced number of colonies in methylcellulose colony forming assays. Insights into the molecular basis of TGIF’s effects were provided by a genome-wide chromatin immunoprecipitation-based elucidation of TGIF target genes. Together, these data suggest that TGIF has a role in regulating the balance between proliferation and differentiation. Reduced TGIF expression could tip the balance toward quiescent leukemic cells (including leukemic stem cells), providing them protection from anti-cycle agents.
Acute Splenic Sequestration in Sickle Cell Disease (SCD): Still a Life Threatening Complication
Authors: Brousse Valentine , Lesprit Emmanuelle , Bernaudin Francoise , Odievre Marie-Helene , Guitton Corinne , Quinet Beatrice , Dangiolo Silvana , De Montalembert Mariane 
Published: April 2020

Abstract
Background: Acute splenic sequestration (ASS) is a life threatening event in SCD during early childhood. Subsequent related mortality has been greatly reduced by both parental education and appropriate management. Moreover SCD screening in neonatal period has allowed early detection contributing to the decrease in fatal attacks.
Objectives: Our aim was to update splenic sequestration epidemiology in a French cohort followed after neonatal screening.
Methods: we reviewed the medical files of SCD children born between 2000–2007 followed since birth in 5 pediatric centres. We included all SCD children diagnosed with acute splenic sequestration, defined as an acutely enlarging spleen with a fall of hemoglobin (Hb) concentration of at least 2g/dL.
Results: A total of 266 episodes of ASS occurred in120 children. There were 69 boys and 51 girls. Genotypes were as follows: 9 S beta° thalassemia, 2 SD-Punjab, 4 SC, 105 SS. In the SS subgroup, median age at first episode was 16 months [1–83] and 34,8% of these first episodes occurred before 12 months of age. Associated symptoms were found in 37 cases (isolated fever n=20, vaso occlusive crisis n=5, identified viral or bacterial infection n= 12) and did not influence the rate of recurrence. Mean Hb level during first crisis was 5.2g/dL [3.3–7]. Mean age at first episode for those who experienced only one episode (n=43) versus more than one episode (n=62) was statistically different (18 months (+/−10) versus 28 (+/−22); p=0.002, Student test). Median interval between first and second episode was 3.5 months [1–31]. 31 patients had 3 or more episodes with a mean interval between second and third interval of 2 months [1–17]. There was no significant difference in the mean age at first episode in children who experienced 2, 3 or more episodes. There was only one fatal case due to acute anemia which occurred in a girl at first recurrence (Hb:2,2g/dL). After the second attack 14(22.5%) patients were splenectomized, 26 patients (41.9%) were started on a transfusion program (followed in 13 cases by splenectomy) and 21 were followed up. Splenectomy was performed at a median age of 4.5years.
Conclusion: These results show that ASS remains a major concern in the management of SCD children. We show a high rate of recurrence and young age at first episode favours this recurrence threat. This study further confirms the effectiveness of early diagnosis and parental education in the decrease of mortality. Prospective studies on spleen dysfunction and additional research on predictive factors are warranted.
Different Subclones of Adult Acute Lymphoblastic Leukemia Detected by Clonal Igh and TCR Markers Behave Differently during Remission and at Relapse
Authors: Davidyan Yulya , Parovichnikova Elena , Surin Vadim , Savchenko Valeryi 
Published: April 2020

Abstract
INTRODUCTION. Immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements are excellent patient–specific targets for the detection of minimal residual disease (MRD) in acute lymphoblastic leukemia (ALL). However they might be unstable during the disease course. False-negative results due to clonal evolution are the major disadvantage of using Ig/TCR gene rearrangements as PCR targets for MRD detection. In order to minimize false-negative results, it is necessary to use more PCR targets for MRD monitoring.
PATIENTS AND METHODS. Bone marrow samples of 34 ALL patients (27 B-ALL, 7 T-ALL) were analyzed for IgH and TCR gene rearrangement by means of PCR method at diagnosis, after induction and consolidation of remission, before and after stem cell transplantation and during maintenance therapy.
RESULTS. Clonal IgH and TCR gene targets for MRD detection were identified in 97% of the patients (33/34). In 70% of the patients (23/33) two or more specific markers for MRD monitoring were detected. Three clonal IgH gene rearrangements were discovered in 2 patients. We wished to investigate whether it was important to monitor two or more targets, because of the dynamics of various markers (subclones) may be different). Prolonged MRD monitoring with 2–3 markers was carried out in 9 patients on different stages of treatment. In 4 of 9 patients (3 precursor B-ALL, 1 pre-T-ALL) the results of MRD detection by 2–3 clonal markers at different time points were similar. And in 5 of 9 patients (3 precursor-B-ALL, 1 precursor T-ALL, 1 B-mature ALL) marker detectability during treatment was dissimilar and not parallel. Of note, 4 of those 5 patients with varying dynamics of different subclones relapsed. Relapse was not observed in the B-mature ALL patient. No relapses were detected in 4 patients with similar dynamics of MRD markers. Bone marrow samples of 8 adult ALL patients were subjected to a detailed analysis of IgH and TCR gene rearrangements by PCR method at diagnosis and relapse. In most patients (7/8) rearrangements identified at diagnosis were present also at relapse. In one patient with precursor-B-ALL one clonal incomplete IgH gene rearrangement (DH-JH) detected at diagnosis was lost at relapse and another one DH-JH rearrangement was preserved. Of note, acute myeloid leukemia was diagnosed at relapse in this patient.
CONCLUSIONS. Comparative PCR analyses of IgH and TCR gene rearrangements did not detect differences between newly diagnosed and relapsed ALL although in a small group of adult patients (unlike childhood ALL). Our data indicate the necessity to monitor MRD in ALL patients with more than one PCR target in order to minimize false-negative results and to predict the course of the disease. The detectability of various MRD markers (subclones) during treatment may differ and this fact could predict a higher probability of relapse.
Copper Levels in Patients with Hematological Malignancies
Authors: Saouli Zoi , Diamantidis Michael D. , Papadopoulos Athanasios , Kaiafa Georgia , Girtovitis Fotios I , Kontoninas Zisis , Ntaios George , Andreadis Charalambos , Savopoulos Christos , Hatzitolios Apostolos 
Published: April 2020

Abstract
INTRODUCTION: Copper is an essential trace element that plays an important role in human biochemistry. Its metabolic pathways involve cellular respiration, peptide biogenesis, connective tissue biosynthesis and antioxidant defense. It is known as an acute phase reactant increasing in response to infection, injure and in chronic inflammatory conditions.
AIM: The aim of this study is to observe the alterations of serum copper levels in patients with various hematological malignancies and also to examine the relation of its levels with the extent of the disease and assess the role of copper determination in staging these patients.
MATERIALS AND METHODS: 77 patients (32 male, 45 female) with various hematological diseases were studied. 50 normal, healthy subjects were studied along. Age ranged from 18–75 years (mean age: 63 years). There were 15 patients suffering from chronic lymphocytic leukaemia (CLL), 17 from non-Hodgkin lymphoma (NHL), 7 from Hodgkin’s disease, 13 from acute myeloid leukaemia (AML), 8 from multiple myeloma and 17 from remainder hematologic malignancies. Copper was measured by flame atomic absorption spectrometry (normal range 0,8–1,3 mg/l). Statistical analysis was conducted by SPSS 12.0. Student’s t-test was used.
RESULTS: Copper levels of the healthy control group were within normal range. When all patients were studied, 51 patients with relapsing disease had elevated copper levels (mean value 1,8 mg/l), whereas 26 patients with remission of their disease had normal copper levels (mean value 1,03 mg/l). Student’s t-test (Sig. two-tailed = p value was 0,000&lt;0,001). When separate disease groups were studied, the results were in accordance with the aforementioned assumption made on all patients: 17 NHL patients (11 relapse − mean copper value = 1,87, 6 remission − mean copper value = 1,12, p&lt;0,001), 15 CLL patients (8 relapse − copper = 1,57, 7 remission − copper = 0,86, p&lt;0,001), 13 AML patients (9 relapse − copper = 1,9, 4 remission − copper = 1,09, p&lt;0,001).
CONCLUSIONS: Our study indicates that elevated copper levels are associated with relapsing hematological malignancies, whereas normal copper levels are associated with remission of the underlying disease. Copper determination might prove to be beneficial in staging such patients, which will lead to proper therapeutic decisions.