bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anticoagulation Clinic Protocol and Electronic Medical Records in Patients Treated with Warfarin: Do They Increase the Likelihood of Achieving Therapeutic INR?
Authors: Patel Urmeel H , Galooshian Liya , Fontem Franklin , Kalavazoff Nadine , Klein Jordan , Agbonavbare Patience , Wert Yijin , Cheriyath Pramil 
Published: October 2019

Abstract
Introduction
Managing patients on warfarin therapy is known to be a challenging task in the outpatient setting. One of the methods used to improve warfarin therapy in the outpatient setting and increase patient compliance and time in therapeutic range (TTR) has been to refer the patient to an anticoagulation clinic. Anticoagulation clinics are used to achieve a higher TTR by using a protocol to standardize the management of warfarin therapy. This study looks into whether the implementation of a protocol to manage warfarin therapy and electronic medical records (EMR) to record the management have any effect on the patients’ TTR.
Method
A retrospective study was completed on patients being managed on warfarin therapy and were a part of an anticoagulation clinic. A chart review was done on ninety-one patients. All INR results were collected on the patients prior to and after the interventions were implemented and included their therapeutic range. The number of days until the INR became therapeutic and the dosage of warfarin required for patients to remain in the therapeutic range were also collected. Chi-square tests were done to analyze the data to determine whether the interventions improved patients’ TTR.
Results
Prior to EMR implementation 62.76% of tests were found to be within therapeutic range; after EMR implementation 58.96% of tests were found to be within therapeutic range with a p-value of 0.0604. Prior to the protocol implementation, 65.41% of tests were within therapeutic range compared to 59.75% of tests within therapeutic range after protocol implementation with a p-value of 0.0409.
Conclusion
Our results showed EMR implementation did not have any effect on the TTR for patients on warfarin therapy. Furthermore, when a protocol was implemented to standardize warfarin therapy and management in the anticoagulation clinic setting, study results revealed the TTR decreased with the standardized protocol with a p-value found to be statistically significant. In conclusion, the data suggests the management of warfarin therapy should be done on an individual patient case-by-case basis rather than a standardized approach to increase TTR.

Disclosures
No relevant conflicts of interest to declare.
A Restrictive Strategy Reduces the Number of Transfused Packed Red Blood Cells in Allograft Recipients
Authors: Mear Jean-Baptiste , Chantepie Sylvain , Gac Anne-Claire , Bazin Agnes , Reman Oumedaly 
Published: October 2019

Abstract
Objectives. The number of transfusion is increasing faster than the rate of new blood donations. Further more, a transfusion excess, causing iron overload may have a deleterious effect on long term survival of patient with a malignant blood disease. We therefore tried to reduce the number of Packed Red Blood Cells (PRBC) by transfusing only one PRBC per transfusion instead of two.
Material and methods. We conducted a prospective monocentric study between January and December 2013, with an historic comparative arm (from January 2010 to December 2012). We compared the number of PRBC transfused per hospital stay between two cohorts receiving only one PRBC per transfusion (Experimental arm or 1PRBC arm) or two PRBC per transfusion (Historical or 2PRBC arm). All patients admitted for remission-inducing therapy for acute leukemia or allogenic hematopoietic stem cell transplant (alloHSCT) aged ≥ 18 were eligible. The study was approved by local ethical committee. Transfusion triggers were hemoglobin lower than 80g/l or symptomatic anemia. Data analysis was performed in intention to treat. Results are mean ± standard deviation.
Results. Seventy-five patients were included in the 1PRBC arm and 194 in the 2PRBC arm. Population distribution for sex, age, pathology and treatment was comparable between the two arms. There was no significant difference of transfused PRBC per hospital stay between the two groups. (7,92±5,39 vs. 9,27±7,42, 15% decrease. p=0,18). However, the restrictive strategy saved 1PRBC per hospital stay (estimated mean of 75 PRBC/year in our center). In the subgroup analysis, alloHSCT recipients from the 1PRBC arm (N=23) received significantly less PRBC than the 2PRBC ones (N=81) (4,13±4,34 vs. 7,51±8,96, 45% decrease. p=0,0058). Savings in this arm is 3 PRBC by hospital stay (estimated mean of 69 PRBC/year in our center). The number of adverse events and symptomatic anemia did not significantly differ between the two arms.
Conclusion. A restrictive transfusion strategy is not inferior to a standard 2PRBC transfusion strategy and saves 1 CGR per hospital stay. This effect is especially patent in alloHSCT recipients. A prospective randomized multicentric study is ongoing to confirm these preliminary results.

Disclosures
No relevant conflicts of interest to declare.
Understanding the Role of Erythrocyte Adenosine Deaminase in the Ribosomopathies
Authors: Narla Anupama , Glader Bertil , Wong Carolyn 
Published: October 2019

Abstract
Diamond Blackfan anemia (DBA) is congenital bone marrow failure syndrome characterized by red cell aplasia and a predisposition to cancer. It was the first disease linked to ribosomal dysfunction with 70% of patients having haploinsufficiency of a ribosomal protein (RP) gene with RPS19 being the most frequently mutated. The 5q- syndrome is a subtype of myelodysplastic syndrome (MDS) also characterized by a severe anemia that is caused by heterozygous loss of RPS14 on chromosome 5q. These patients also have a predisposition to cancer. The reciprocal relationship between these two diseases, which are now collectively known as the ribosomopathies, has spurred interest in how we may be able to better understand the pathophysiology of these ribosomopathies to broaden therapeutic options, and to improve diagnosis.
Erythrocyte adenosine deaminase (eADA) levels have been used for last three decades in the diagnosis of Diamond Blackfan anemia based on the finding in 1983 that eADA enzyme levels are significantly elevated in patients with DBA. It is now known the eADA levels are elevated in >75% of patients with DBA. Furthermore, it has a sensitivity of 84%, specificity of 95% and positive and negative predictive values of 91% for the diagnosis of DBA compared with other inherited bone marrow failure syndromes. Our goal was to study the levels of eADA in patients with the 5q- syndrome to determine whether they were elevated (suggesting that eADA may be specific to ribosomal haploinsufficiency in general) or normal (suggesting that eADA may be specific to DBA).
Under a Stanford approved IRB, we are testing adult patients with the 5q syndrome who have not been transfused in the previous 3 months (which would affect the results of the test) and who have a confirmed deletion of the 5q- region by cytogenetics. To date, all of the 4 MDS samples, sent to us from collaborating hematologists, have had a normal eADA level. These findings suggest that elevation of eADA may be specific to DBA and not a general feature of ribosomal haploinsufficiency although our sample size is small and we plan to test additional samples.

Disclosures
No relevant conflicts of interest to declare.
Hydrocortisone does Not Influence in Vitro Glucocorticoid Sensitivity of Acute Lymphoblastic Leukemia Blasts
Authors: Warris Lidewij T. , van den Heuvel-Eibrink Marry M. , Ariës Ingrid M. , Pieters Rob , van den Akker Erica L.T. , Den Boer Monique L. 
Published: October 2019

Abstract
Introduction: Dexamethasone-induced neuropsychological side effects on mood, behavior and cognition seriously affect quality of life in children with acute lymphoblastic leukemia (ALL) during a long treatment period. Based on recent studies in animals, we hypothesized that these neuropsychological side effects are mediated by dexamethasone-induced cortisol depletion of the mineralocorticoid receptor (MR) in the brain. Therefore, we hypothesize that these side effects could be ameliorated by an intervention with hydrocortisone. For clinical application settings however, an absolute prerequisite is that MR activation does not interfere with the efficacy of the glucocorticoids, dexamethasone and prednisolone, on ALL cells.
Materials and Methods: To investigate responsiveness of leukemic cell lines and fresh patients’ leukemic cells to dexamethasone and prednisolone in the presence of hydrocortisone, MTT-assays were performed. In addition MR and the glucocorticoid receptor (GR) expression on leukemic cells of different ALL subtypes was studied with a microarray-based gene expression profiling and validated by quantitative real-time PCR.
Results: Leukemic cells expressed the MR at a very low level with a significantly higher (P≤0.001) expression in ETV6-RUNX1+ patients (median: 160.7 [AU] of fluorescence intensity, range: 38.1 - 760.6 [AU]) versus other ALL subtypes (median: 41.8 [AU] of fluorescence intensity, range: 25.1 - 276.2 [AU]). MR expression did not differ between glucocorticoid resistant and sensitive patients’ cells. Hydrocortisone addition did not affect glucocorticoid sensitivity of leukemic cell lines and patients’ leukemic cells of different leukemic subtypes also including ETV6-RUNX1+. Glucocorticoid sensitive patients’ cells became significantly more sensitive by hydrocortisone addition (prednisolone: P≤0.01, dexamethasone: P≤0.05).
Conclusion: This present study shows that hydrocortisone does not interfere with efficacy of dexamethasone and prednisolone in vitro. These findings support a clinical randomized trial to study whether addition of hydrocortisone decreases the neuropsychological side effects of dexamethasone in children with ALL.
Acknowledgments: The financial support of the KiKa® (Kinderen Kankervrij) foundation is highly appreciated.

Disclosures
No relevant conflicts of interest to declare.
Established Standards of Minimal Residual Disease Detected By Multiparametric Flow Cytometry in Acute Leukemia
Authors: Jing Hui , Huang Fen , Yi Zhengshan , Zheng Zhongxin , Wei Xiaolei , Xie Muchen , Hao Xiaoxiao , Feng Ru 
Published: October 2019

Abstract
Purpose
To establish a method for detecting minimal residual disease (MRD) by eight color flow cytometry which is stable, repeatable and accurate quantitation.
Method
According to the ratio of 10%, 1%, 0.1%, 0.01% and 0.001%,to analyze sensitivity of the method by successively mixing the cell lines (Kasumi, KG-1a) and primary acute leukemic bone marrow cell were mixed with normal bone marrow cells. In order to ensure the specificity of the test results, we increased antibody number to eight color combinations of antibodies to adjust fluorescence compensation value after labeling antibody separately in each channel. To verify the feasibility of standardization, standardized test were in 25 bone marrow samples of acute leukemia.
Result
In standard conditions of detection and sensitivity of 10-5could be detected by eight color flow cytometry. In our study there were 25 cases of acute leukemia, including 14 patients with acute myeloid leukemia and 11 patients with acute B-lymphoblastic leukemia. 23 of 25 cases were detected specific leukemia associated immunophenotypes (LAIP) at diagnosis. 20 patients could be detected the original LAIP, and LAIP of 3 patients changed after remission induction therapy. To analyze the relationship between the clinical data and MRD level, the result showed that the type of LAIP had significant influence on level of MRD. After remission the level of MRD in patients who expressed cross lineage and non-synchronous antigens at diagnosis was significantly higher than those who did not express (P=0.003, P=0.006).
Conclusion
We established the standardized conditions of minimal residual disease detected by multiparametric flow cytometry to ensure the accuracy and specificity of the test results. It has important significance to confirm that manifestations of LAIP were consistent with the outcome in patients with acute leukemia.

Disclosures
No relevant conflicts of interest to declare.
Paired Analyses of Diagnostic and Relapse Samples of MLL rearranged Infant Acute Lymphoblastic Leukemia Reveals Potential Therapy-Resistant Genomic Alterations
Authors: Buijs Arjan , Stevens-Kroef Marian JPL , Sonneveld Edwin , van der Veken Lars T. 
Published: October 2019

Abstract
Infant acute lymphoblastic leukemia (ALL) (less than one-year-old) is a rare, aggressive disease, with unique biological and clinical features. It is associated with 11q23 MLL rearrangements (MLL-R), and a high relapse risk. In contrast, in childhood ALL (age 1-18 years) the majority survives beyond 5 years, and only 15-20% of patients relapse. The genomic landscape in the latter group has been investigated quite extensively, and is has proven to be of diagnostic and prognostic significance. Paired diagnostic and relapse samples have identified frequent microdeletions in B-cell differentiation and cell cycle regulating genes IKZF1, EBF1 and CDKN2A/B. Alterations in these genes, either at diagnosis or relapse are linked to therapy-resistance. In contrast, data on copy-number alterations in infant ALL, particularly at relapse, are very limited. Therefore, we investigated two infant ALL at diagnosis and relapse by molecular cytogenetic analyses including high-density SNP array.
A six-months-old boy was diagnosed with pro B-ALL. Molecular cytogenetic analyses revealed a t(4;11) MLL-AFF1 positive karyotype. SNP array resulted in a balanced profile. After a MUD-SCT the ALL relapsed at age 1.1-years. Cytogenetics demonstrated the t(4;11) stemline, and evolution with two related sidelines, one with a dic(1;19) and another with an unbalanced t(1;18), both resulting in 1q gain. In addition, SNP array analysis revealed homozygous loss of 7p12.2 IKZF1 due to an overlapping and an intragenic exon 2-3 deletion.
The second case, a 3-months-old boy with pre B-ALL, showed a complex t(11;19) MLL-MLLT1 positive karyotype. Microarray analysis resulted in a balanced profile. At age one-year the ALL relapsed after a sibling-SCT, with the complex karyotype. SNP array showed a chimeric profile with only two small heterozygous 19p13.3 deletions, one including TCF3.
In childhood ALL drug resistant blasts at relapse are probably subclonal at diagnosis, or develop during therapy, with frequent microdeletions of B-cell differentiation regulating genes IKZF1 and EBF1. These alterations are found particularly in MLL-wt ALL, whereas MLL-R ALL is associated with epigenetic perturbations. Interestingly, in our two cases of infant MLL-R ALL we observe, at relapse only, microdeletions of B-cell differentiation regulating genes IKZF1 and TCF3. It is of importance to study more paired cases to further define the mutational landscape of this unique, but ill-fated subtype of ALL.

Disclosures
No relevant conflicts of interest to declare.
Defining Criteria for Diagnosis of Occult Lymphomatous Involvement in Cerebrospinal Fluid
Authors: Mocikova Heidi , Klanova Magdalena , Spacek Martin , Pytlik Robert , Kozak Tomas , Trneny Marek , Pospisil Vit 
Published: October 2019

Abstract
Introduction: Currently, there is no consensus regarding diagnosis and treatment of occult lymphomatous menigeal involvement of cerebrospinal fluid (CSF) in patients with systemic non-Hodgkin lymphomas (NHL), especially in patients with minimal number of clonal cells detected by flow cytometry (FCM) or by cytology.
Aim of the study: To describe a cohort of patients with occult lymphomatous involvement in cerebrospinal fluid including the diagnostic methods as well as management.
Patients and methods: CSF at diagnosis of B-NHL was examined by FCM, cytology, biochemistry and microRNA analysis in a cohort of 62 patients (systemic DLBCL N=45, MCL N=15, Burkitt lymphoma N=2) between 2010 and 2013. Occult meningeal involvement was defined by: a/ FCM: absolute positive number of clonal cells <20 and concomitant negative finding by cytology; b/ FCM negative for clonal cells and concomitant positive finding by cytology; c/ by abundance of increased levels (≥ 200% of the threshold levels) of oncogenic microRNAs (members of miR-17-92 cluster and miR-21, evaulated by Taq-Man RT PCR) in cerebrospinal fluid in patients either passing a/ or b/. The threshold of individual microRNA abundance was defined by statistical analysis of patients with or without CNS involvement. The patients qualified for occult meningeal involvement were considered to be at high risk of CNS relaps. As a control group, the patients with elevated oncogenic microRNAs and negative FCM or cytology of CSF (N=10), were used. All patients received some form of CNS prophylaxis as a part of standard first line treatment.
Results and conclusions: According to described criteria we identified 8 patients with occult meningeal involvement at diagnosis (systemic DLBCL N=4, MCL N=3, Burkitt lymphoma N=1) out of 62 patients: 3 with negative FCM and positive cytology (2-14 cells/ul); and 5 with positive FCM <20 clonal cells and negative cytology, 3 out of them with positive microRNAs. None of these patients with occult meningeal involvement relapsed/progressed into CNS within 12 months. In contrast three out of ten control patients (characterized by elevated oncogenic microRNAs in CSF, but negative for FCM and cytology) relapsed to CNS within 6 months after diagnosis. None of ”triple” negative (FCM, cytology, microRNA) patients (N=44) developed clinically manifest CNS involvement.
These results suggest that examination of oncogenic microRNA in CSF at diagnosis is more sensitive method than FCM and cytology of CSF to detect the patients with occult CNS involvement and higher risk of CNS involvement and this should be reflected in treatment strategy in further clinical trials.
Grants: GACR305 13-12449P, UNCE204021, PRVOUK: P24/LF1/3, P27/LF1/1, P 27/2012 LF3

Disclosures
Spacek: Roche: Consultancy, Travel grants Other.
Low Blood Absolute CD4 Counts Is Associated with Inferior Progression Free Survival in Diffuse Large B-Cell Lymphoma Independent of Age and IPI
Authors: Al-Saleem Tahseen I. , Dulaimi Essel , Millenson Michael M. , Smith Mitchell R. , Judd Julia , Li Tianyu , Borghaei Hossein 
Published: October 2019

Abstract
Tumor-infiltrating immune cells influence diffuse large B-cell lymphoma (DLBCL) outcome. Relatively little is known about the significance of peripheral blood immune cell counts (obtained by generally available flow cytometry) on DLBCL behavior
Patients and methods: 45 newly diagnosed DLBCL patients enrolled in an institutional protocol had blood pretreatment multicolor flow cytometry performed and immune cell counts recorded. The M/F ratio was 24/21, age 19-88, median 64; stage I: 11, II: 13, III: 6 and IV: 15. Thirty two had low/ intermediate International Prognostic Index (IPI) score (0-2) and 13 had 3+ IPI. One patient was HIV+. Thirty seven (82%) received immuno-chemotherapy and 8 had chemotherapy and/or irradiation.
Statistical Methods: The outcomes of the study were progression free survival (PFS) and overall survival (OS). Kaplan-Meier estimation method and Log-rank test were used in the univariate analysis. The Cox proportional hazard model was used for multivariable analysis (MVA). All analyses were done via SAS 9.2.
Results: Mean absolute CD4 cell count (ACD4C) was 450/c.mm and the median about 400. After follow up of 0.8 to 152 months (median: 73), 25 (56%) were still alive.
Univariate analysis: significant predictors to PFS were: age (HR=1.05, 95%CI: 1.02-1.09, p=0.005), ACD4C (HR= 0.998, 95% CI: 0.966-1.000, p= 0.023] and IPI (HR=0.05, 95%CI: 0.995-1.89, p= 0.054). But for OS ACD4C was only marginally significant (p= 0.083). Absolute lymphocyte count (ALC), CD8 and [CD3-C56+ (NK)] counts did not correlate with OS or PFS.
When analyzed as a binary variable with cutoff of 450/cmm, the 18 patients with high ACD4C had better 5 year PFS, 88% vs. 52% (p= 0. 023), figure (1), and OS, 88% vs. 59% (0.054) than the 27 with low ACD4C. Age, IPI groups (low /intermediate versus high) and ALC also correlated with PFS and OS, but not the CD8 or NK cell counts.
MVA with age as a continuous variable, IPI groups and ACD4C of 450/cmm; age and ACD4C only were significant for PFS, (p= 0.008 and 0.036 respectively). For OS age was the only significant variable (p=0.017). ALC, CD8 and NK cell counts did not correlate with PFS or OS.
Conclusion: Though the series contains more early stage patients than usual, blood ACD4C seems to be a predictor of PFS and to a lesser extent OS in DLBCL independent of age and IPI. If confirmed in a larger prospective study of uniformly treated patients ACD4C may serve as an immunological marker for DLBCL biological behavior.
Figure1: Progression Free Survival Figure1:. Progression Free Survival

Disclosures
No relevant conflicts of interest to declare.
The Impact of Early Molecular Response in Event Free Survival in Patients with Chronic Myeloid Leukemia Treated with Imatinib
Authors: Fogliatto Laura , Capra Marcelo Eduardo Zanella , Shaan Mariza , Costa Tito Vanelli , Torriani Mayde Seadi , Contin Luis Carlos Zanandrea , Breunig Raquel , Fassina Katia , Fernandes Mario Sérgio , Almeida Denise , Schilling Marco Antônio , Hellwig Tânia , Daltoe Tiago , Zardo Adriana , Moschen Mariangela , Nene Moema , Silveira Juarez Fontoura , Soares Tahiane Brum , Daudt Liane Esteves , Friedrisch João , Silla Lucia 
Published: October 2019

Abstract
Background
Monitoring response to TKI therapy is one of the key management strategies of chronic myeloid leukemia (CML). Early molecular response to first-line TKI therapy is emerging as an effective prognostic factor indicator of long-term durable response and survival.
Objectives
We conducted a study to evaluate the importance of the early molecular response (EMR) at 3, 6 and 12 months (mo), and 3-year event free survival (EFS).
Methods
This is a retrospective study in a cohort of pts with chronic myeloid leukemia chronic phase (CP) enrolled in 14 Hematology centers in South Brazil. All pts received imatinib 400mg as first or second-line therapy. Patient evaluation and response criteria followed the ELN recommendations. EFS was measured from the start of imatinib to the date of any of the following events while on therapy: death from any cause, loss of complete hematologic response, loss of complete cytogenetic response, discontinuation of therapy for toxicity or lack of efficacy, or progression to accelerated phase or blastic phase.
Results
We analyzed data from 517 pts with CML-CP diagnosed since 1990. After a median observation time of 46 months, 5-year overall survival (OS) was 86% and 5-year event-free-survival was 53%. At 3 mo, EFS was 72,5% for 46 pts with BCR-ABLIS ≤10% compared to 58% for 14 pts with BCR-ABLIS >10% (p<0,07). Similarly, when EMR was analysed at 6 mo, the EFS was 81% for 75 pts with BCR-ABLIS ≤1%, while 31% of EFS was achieved for 38 pts with BCR-ABLIS >1% (p<0,001). At 12 mo, the 3-year EFS was 86% for 65 pts with with BCR-ABLIS ≤0,1% compared to 54% for pts with BCR-ABLIS>0,1% (p<0,001).
Conclusions
A significant proportion of pts achieve ERM after 3,6 and 12 mo of imatinib therapy with better 3-year EFS. ERM may could identify those pts more likely to have a favorable outcome.

Disclosures
No relevant conflicts of interest to declare.