bluuebunny/crossref_metadata_2025_split huggingface dataset:
Flow Cytometric Measurement of the Initial In Vivo Response to Prednisone Provides New Prognostic Information in Childhood Acute Lymphoblastic Leukemia (ALL)
Authors: Gaipa Giuseppe , Maglia Oscar , Sala Simona , Marino Noemi , Silvestri Daniela , Valsecchi Maria Grazia , Biondi Andrea , Conter Valentino 
Published: October 2019

Abstract

Background The initial in vivo response on corticosteroid therapy (<1000 blasts/mmc at day 8 after exposure to Prednisone) is considered a prognostic predictor to qualify patients at higher risk of relapse (Riehm H et al, Klin. Padiat. 199, 1986). This parameter has been prospectively validated in several BFM-oriented trials providing evidences to be a robust predictor of disease recurrence even in specific subgroups of ALL (Schrappe M et al, Klin. Padiat. 2013). Evaluation of day8 prednisone response is assessed by morphological evaluation of peripheral blood (PB) smears, however this approach may have several limitations such as poor quality of the smears, operator- dependent variability and accuracy, poor reproducibility between centers.
Methods We studied a total of 543 (of 648 eligible) patients enrolled in the AIEOP-BFM ALL 2000 study between January 2001 and December 2011 in the centers of Monza and Padova (275 and 268 patients respectively). PB collected at day+8 of induction phase was analyzed by multiparametric flow cytometry (FCM) to assess blast immunophenotyping by standard methods developed in the context of the I-BFM Flow network (Dworzak MN et al, Cytometry part B, 2008).
Results Five hundred-seven patients (93.4%) had <1000 blasts/mmc as assessed by FCM, whereas 36 (6.6%) had ≥1000 blasts/mmc. Five-year Event Free Survival (5 yrs EFS) was 84.8% and 76.4% respectively (p-value =0.01). We further investigated the absolute count by sub-grouping the patients in three levels: i) 0<100 blasts/mmc (n 416), ii) ≥100<1000 blasts/mmc (n 91), and iii) ≥ 1000 blasts/mmc (n 36). 5 yrs EFS was 86.8%, 75.6% and 76.4%, respectively (p-value group a vs group b was 0.001), see Figure. Five years Cumulative Incidence of Relapse (5yrs CIR) was 11.4%, 21.1% and 17.9%, respectively (p-value group a vs group b was 0.003). When we excluded the high-risk (HR) patients from the analysis, those in the group with ≥100<1000 blasts/mmc (n71) maintained a significant worse outcome as compared with the group of patients with 0<100 blasts/mmc.
Conclusions We identified a group of 71 patients (13% of total) with non-HR characteristics and with ≥100<1000 blasts/mmc at day8, showing significant worse outcome as compared to patients with <100 blasts/mmc, that could benefit of a more intensive treatment. These Analyses will be validated on a larger cohort of patients. FCM is more accurate and reproducible as compared to morphology and should be considered as an alternative method for the evaluation the initial in vivo response to corticosteroid therapy and possibly for a further refinement of treatment stratification of children with ALL.
Figure. Figure.

Disclosures
No relevant conflicts of interest to declare.
Proteomic and Biological Analysis of Myeloma Cell Derived Extracellular Vesicles
Authors: Hoelzinger Dominique B , Quinton Sophia J , Walters Denise K , Tschumper Renee C , Jelinek Diane F 
Published: October 2019

Abstract
Intercellular communication between multiple myeloma (MM) cells and the normal bone marrow stroma leads to a modification of the bone marrow microenvironment, which favors tumor progression. New developments in extracellular vesicle (EV) research suggest that this diverse population of vesicles, released by cancer cells including MM cells, express transmembrane proteins and carry cargo that can modify recipient cells in myriad ways. In particular, tumor-derived EVs have been shown to create permissive microenvironments that lead to metastatic colonization by circulating tumor cells. As we have previously shown that MM EVs can enhance proliferation of recipient MM cells, we hypothesize that MM EVs can potentially play a much larger role in MM development and progression. In order to understand the scope of potential EV roles in MM, we executed a comprehensive proteomic analysis of the cargo of MM EVs. We isolated EVs from patient derived MM cell lines that represent the most common genetic variants of this tumor, and used in vitro generated plasma cells (IVPCs) as a reference population. In a first pass analysis, we selected proteins that were expressed ≥3 fold higher in MM EVs than in IVPC EVs, and this analysis identified 306 proteins. Of interest, included in the 306 differentially proteins were several involved in the regulation of cell adhesion such as members of the a disintegrin and metalloprotease domain (ADAM8, 9, 10, 13, 15 and 22) family, which are also associated with inhibition of cell proliferation. Moreover, CEACAM1, PTPRK, and CDH2, which are also linked to cellular adhesion, were also expressed at a higher level in MM EVs. Various proteins linked to myeloma cell biology were likewise found to be over-represented in MM EVs, and these include BCMA, ITGAV, ITGB5, IL6ST (gp130), CD276 (B7-H3), and CD28. As we are most interested in biologically relevant and actionable proteins present uniquely in MM derived EVs, we filtered from our data proteins that were also present in EVs from IVPCs. We further filtered out proteins known to be present in EVs from normal cells. This filtering strategy reduced the number of interesting candidates to 8, which included CD28, MET, TRKC, and ADAM15. Thus far, we have confirmed the presence of these 4 proteins in a panel of MM EVs, and we are currently in the process of validating additional candidate cargo proteins for their biological role in enhancing tumor cell proliferation and/or protection from apoptosis. In summary, EV proteomic analysis of cell lines representing MM genetic subtypes can lead to the identification of biologically relevant proteins transported systemically by EVs as well as suggest novel biomarkers that are easily detectable in plasma and may permit earlier recognition of disease progression in patients with MM.

Disclosures
No relevant conflicts of interest to declare.
Evaluation of the Risk of Atrial Fibrillation/Flutter Among Patients Initiating Ibrutinib
Authors: Nohria Anju , Rosenblatt Lisa , Pan Xianying , Sharma Arpita 
Published: October 2019

Abstract
INTRODUCTION:
Ibrutinib is a Bruton's tyrosine kinase inhibitor that is used to treat chronic lymphocytic leukemia and other hematologic malignancies. Atrial fibrillation/flutter (AF) is emerging as an adverse effect of ibrutinib therapy. The objective of this analysis was to evaluate the incidence of new AF in a real-world sample of patients initiating ibrutinib and exploring potential risk factors of AF in this population.
METHODS:
A retrospective cohort study of patients (age>=18) initiating ibrutinib between 01 Nov 2013 and 30 Sep 2017 was conducted using four US administrative claims databases. The databases used were MarketScan - Commercial and Medicare Supplemental Database, Optum Clinformatics Data Mart, PharmetricsPlus Adjudicated Claims Database and Humana. Patient cohorts were identified independently from each of the databases and were combined for pooled analyses after ensuring a minimum patient overlap of less than 5% among databases. The date of first prescription of ibrutinib was considered as the index date. Patients were followed from the index date to the end of index ibrutinib therapy (ibrutinib discontinuation date, follow-up end, or study end, whichever was earliest) to identify the diagnosis of new AF. Patients with an AF diagnosis prior to the index date were excluded. Baseline characteristics (including demographics, comorbidities, type of cancer and Charlson Comorbidity Index (CCI) score) were evaluated. Incident rates were calculated as number of AF events per 100 person-years and were stratified by age and gender. Cox regression models were used to estimate hazard ratios and assess potential risk factors for AF among patients receiving ibrutinib.
RESULTS:
The study examined outcomes in 7,276 patients treated with ibrutinib, including 4,650 (63.91%) males and 2,626 (36.09%) females, followed for a median duration of 161 days (~5.3 months). The overall incidence rate of AF was 12.5 per 100 person-years (Table 1). The median duration until AF diagnosis was 117 days (~4 months). Males were at higher risk of developing AF than females; a similar trend was observed in patients age >75 compared to younger patients. Ibrutinib patients with congestive heart failure (CHF), peripheral vascular disease (PVD) or a moderate CCI score (3-4) at baseline were at higher risk of developing AF.
CONCLUSION:
The incidence of AF in patients treated with ibrutinib is substantial. Older age, male gender, and baseline comorbidities (CHF and PVD) notably affect the risk of developing AF in these patients. AF should be considered when monitoring for adverse events in patients treated with ibrutinib.

Disclosures
Nohria: Takeda Oncology: Consultancy; Amgen: Research Funding. Rosenblatt:Bristol-Myers Squibb: Employment, Equity Ownership. Pan:Bristol-Myers Squibb: Employment, Equity Ownership. Sharma:Mu Sigma: Employment; Bristol-Myers Squibb: Consultancy.
Impact of Length of Stay on Hospital-Associated Venous Thromboembolism (VTE)
Authors: Slostad Jessica A , Slostad Brody , Crusan Daniel , Petterson Tanya , Bailey Kent , Ashrani Aneel A. , Heit John A. 
Published: October 2019

Abstract
Introduction:
Hospitalization-associated VTE attack (incident plus recurrent VTE) rates over the 6-year period, 2005-2010, did not change significantly despite achieving near-universal in-hospital VTE prophylaxis; 75% of these VTE events occurred after hospital discharge with a median of 19.5 days from hospital discharge to VTE. The median durations of hospitalization and in-hospital prophylaxis were 3 days and 70 hours, respectively, suggesting that VTE prophylaxis was inadequate. However, the hospital population that would benefit most from post-hospitalization VTE prophylaxis is uncertain. Our study aim was to test hospital length of stay (LOS) as a potential predictor of post-hospital-discharge incident or recurrent VTE.
Methods:
Using the resources of the Rochester Epidemiology Project, we identified all unique Olmsted County, MN residents hospitalized at least once at a Rochester, MN Mayo Clinic hospital and all such residents with objectively-diagnosed occurrence of first or recurrent VTE during hospitalization or within 92 days after hospital discharge, 2005-2010. We tested LOS as a potential predictor of post-hospital-discharge VTE (conditional on surviving to hospital discharge free of VTE) using the Anderson-Gill version of Cox regression modeling and adjusting for age, sex, any surgery performed during that hospitalization, and Charlson Comorbidity Index calculated from conditions recorded from 1/1/2005 until the day of hospital discharge.
Results:
Over the period, 2005-2010, 31,588 unique Olmsted County residents were hospitalized at least once at a Rochester Mayo Clinic hospital. The distribution of LOS was: 1-2 (3.8%), 3 (24.2%), 4 (23.3%), 5 (16.4%), 6 (8.8%), 7-9 (12.4%), 10-19 (8.4%) and 20+ (2.3%). Of the 253 VTE events identified within 92 days post-hospital discharge, 6, 29, 31, 38, 38, 53, 42 and 16 had been hospitalized for 1-2, 3, 4, 5, 6, 7-9, 10-19 and 20+ days, respectively. The hazard ratios (HR) for post-hospital-discharge VTE were similar for hospital LOS ≤4 days; compared to LOS ≤3 days, the HRs were significantly increased for hospital LOS of 5 (HR=1.78), 6 (HR=2.86), 7-9 (HR=2.71), 10-19 (HR=3.16) and 20+ (HR=4.20) days (Table 1).
Conclusions:
The adjusted hazards of post-hospital discharge VTE for hospital LOS > 4 days were significantly increased 1.8 to 4.2-fold compared to LOS ≤3 days, suggesting that hospital LOS may be useful for identifying hospitalized patients suitable for longer duration VTE (including post-discharge) prophylaxis. Future studies should be aimed at identifying additional predictors of post-hospital-discharge VTE such that extended prophylaxis can be targeted to those patients who would benefit most.

Disclosures
No relevant conflicts of interest to declare.
Targeting the MTF2-MDM2 Axis Sensitizes Refractory Acute Myeloid Leukemia to Chemotherapy
Authors: Jrade Hani , Maganti Harinad B , Cafariello Christopher , Porter Christopher J , Yockell-Lelièvre Julien , Battaion Hannah L , Khan Safwat T , Howard Joel P , Perkins Theodore J , Sabloff Mitchell , Ito Caryn Y , Stanford William L. 
Published: October 2019

Abstract
Next generation sequencing of acute myeloid leukemia (AML) patient samples has enabled more granular risk stratification of patients; however, refractory AML patients can be found across all risk groups, suggesting that non-genetic lesions regulate chemoresponsiveness. Consistent with this hypothesis is the finding that many of the mutated AML driver genes are encode epigenetic modifiers. Thus, unraveling the epigenetic dysregulation in AML is critical to better understand disease initiation and progression, as well as develop targeted therapies. Metal Response Element Binding Transcription Factor 2/Polycomblike 2 (MTF2/PCL2) plays a fundamental role in recruiting the Polycomb repressive complex 2 (PRC2) to chromatin and we show that it is commonly silenced in primary AML patient cells at diagnosis. Furthermore, the loss of MTF2 in hematopoietic stem and progenitor cells (HSPCs) leads to an altered epigenetic state that underlies refractory AML. By implementing unbiased systems analyses, we identified the E3 ubiquitin ligase MDM2 that inhibits p53 as a direct target of MTF2-PRC2. MTF2 deficiency leads to over-expression of MDM2 and inhibition of p53-mediated cell cycle regulation and apoptosis, leading to chemoresistance and refractory AML. Targeting this dysregulated signaling pathway by MTF2 overexpression or MDM2 inhibitors sensitized refractory patient leukemic cells to induction chemotherapeutics and prevented relapse in AML patient-derived xenograft (PDX) mice. Therefore, we have uncovered a direct epigenetic mechanism by which MTF2 functions as a tumor suppressor required for AML chemotherapeutic sensitivity and identified a potential therapeutic strategy to treat refractory AML.

Disclosures
Sabloff: Celgene: Membership on an entity's Board of Directors or advisory committees.
Incidence, Clinical Characteristics and Outcome of Cardiac Toxicity in Elderly Patients with Diffuse Large B-Cell Lymphoma
Authors: Liu Wei Ping , Xu Yan Feng , Xie Yan , Wang Xiaopei , Song Yuqin , Zhu Jun 
Published: October 2019

Abstract
Backgroud:
Cardiac toxicity is a life-threatening complication in elderly patients with lymphoma, which lead to a delay or premature termination of chemotherapy.
Methods:
A total of 462 consecutive patients with diffuse large B-cell lymphoma over 60 years old between 2007 and 2017 were reviewed. Of these, 87 patients were excluded from the study. Finally, 375 lymphoma patients were included. Data about general information, clinical feature, laboratory examination, pathological results, therapeutic methods and cardiac toxicity were collected by case retrieval system. Cardiac toxicity was graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE).
Results:
The incidence of cardiac disorders was 5.3% (20/375). The median number of chemotherapy cycles before cardiac toxicity was 1 (range, 1-4). Ventricular arrhythmia was the most frequent cardiac disorder (n=6), followed by palpitations (n=4), left ventricular systolic dysfunction (n=3), heart failure (n=3), atrial fibrillation (n=2), myocardial infarction (n=1) and paroxysmal atrial tachycardia (n=1). At the end of treatment, grades 3 to 5 cardiac events were observed in 8 patients. In a multivariate Cox regression analysis, ECOG performance status ≥2 and history of cardiovascular disease were identified as risk factors for IP. The cumulative incidence of cardiac disorders were 2.3% (6/266) for patients without risk factors, 11.6% (11/95) for patients with 1 risk factors, and 21.4% (3/14), respectively.
Conclusion:
Cardiac toxicity is not rare in elderly patients with lymphoma, and a comprehensive management strategy is needed.

Disclosures
Song: Peking University Cancer Hospital (Beijing Cancer Hospital): Employment. Zhu:Beijing Cancer Hospital: Employment.
Compound Heterozygous Nonsense Mutations Leading to Hereditary Deficiency of Coagulation Factor XI in a Chinese Pedigree
Authors: Li Qian , Zeng Hui , Xu Yong , Zhou Min , Chen Bing , Zhou Rong-Fu 
Published: October 2019

Abstract
The objective is to identify the gene mutations responsible for the deficiency of factor XI (FXI) in a Chinese pedigree. The FXI activity was tested with clotting assay. The F11 gene was amplified by PCR with direct sequencing. ClustalX-2.1-win and three online bioinformatics softwares were used to study the conservatism and harm of the mutation. The proband was a 70-year-old male and had a prolonged APTT of 67.8s. The corrected APTT was 28.3s and he had reduced FXI: activity of 0.8%. His son and daughter had normal APTT of 26s and 27.3s and FXI:C of 72% and 75%, respectively. DNA sequencing analysis showed the proband carried a compound heterozygous g.841C>T and g.1556G>A mutation , resulting in Ser281Stop and Trp519Stop, respectively, which caused premature termination of transcription in the F11. His son had the heterozygous g.841C>T mutation of F11 and his daughter had the heterozygous g.1556G>A mutation of F11. The three bioinformatics softwares indicated that the mutation had affected the function of the protein. The two nonsense mutations had been reported previously in different patient, but this is the first time to be reported in the proband, which was responsible for the decrease of FXI: activity.

Disclosures
No relevant conflicts of interest to declare.
98% IGHV Gene Identity Is Still the Optimal Cutoff to Predict the Prognosis of Chronic Lymphocytic Leukemia Patients in China
Authors: Xia Yi , Shi Ke , Sun Qian , Qiao Chun , Zhu Huayuan , Wang Li , Fan Lei , Xu Wei , Li Jianyong 
Published: October 2019

Abstract
Background: Immunoglobulin heavy chain variable region (IGHV) has been an important prognostic factor for chronic lymphocytic leukemia (CLL) for decades. 98% being a cut-off value for IGHV is a mathematical choice and researches on the best cut-off value have never been stopped. Chinese CLL patients are known to differ from Caucasian CLL patients on both clinical and genetical features. However, the optimal cutoff for IGHV mutational status has not yet been studied in this particular ethnic group.
Method: We carried out a study on 595 Chinese CLL patients in order to find out whether 98% is the best cut-off value for IGHV in Chinese CLL patients. Genomic DNA from peripheral blood or bone marrow was subjected to PCR amplification following the IGH Somatic Hypermutation Assay v2.0 protocol (InVivoScribe). Sequences were aligned to ImMunoGeneTics/V-QUEry and Standardization (IMGT/-VQUEST) database.
Result: 600 sequences were received after IGHV rearrangement sequencing. IGHV3-23, IGHV4-34, IGHV3-7, IGHV4-39 and IGHV1-69 were the most frequently used IGHV genes. 352 (58.7%) cases were IGHV-mutated while 248 (41.3%) cases were IGHV-unmutated if the classical 98% classification by ERIC was used. In order to determine the optimal cut-off value, we used 1% as the interval to divide the entire cohort into 7 groups according to the mutational rate, which were <95%, 95%-95.99%, 96%-96.99%, 97%-97.99%, 98%-98.99%, 99%-99.99% and 100% respectively. Binet A patients had a relatively indolent course of disease and cases with different IGHV mutational rates had no significant differences in time to first treatment (TTFT) apart from truly unmutated (100%) cases. For the whole study cohort, significant difference appeared at 98% interval (P<0.001 and P=0.005 for TTFT and OS respectively) while intervals less than 98% had no significant difference compared with the <95% group. Similarly, there was no clear dissimilarities among 98%, 99% and 100% intervals (Table 1a and b). All the other prognostic factors including del(17p), del(11q), TP53 mutation, MYD88 mutation, NOTCH1 mutation, SF3B1 mutation, CD38, ZAP-70, Binet staging, gender, β2-microglobulin and EBV-DNA were differently distributed between group <98% and group ³98%, but not among subgroups in ³98%. In multivariate analysis, the 98% IGHV was also an independent prognostic factor for TTFT and OS.
Conclusion: 98% is the optimal cutoff value for IGHV mutational status to predict the prognosis of CLL patients in China.
Table 1. Table 1.

Disclosures
No relevant conflicts of interest to declare.
Predictors of Adverse Outcome in Sickle Cell Disease Patients from Oman
Authors: Alkindi Salam , AlJadidi Salma , Al Adawi Safa , Pathare Anil 
Published: October 2019

Abstract
Introduction: Sickle cell disease (SCD) is a major public health problem in Oman with high morbidity and mortality. The ability to identify the risk factors that are associated with mortality among SCD patients would permit accurate prognostication and provide an opportunity to use effective prophylactic management.
Objective: The study aimed at identifying the risk factors associated with mortality in SCD patients by studying the clinical course of 86 patients who died at two tertiary care hospitals in Oman.
Methods: We analyzed the electronic records of 86 SCD patients who died between 2006 to 2016. These data included cardiac parameters, SCD manifestations like frequency of painful crisis, acute chest syndrome, splenic and hepatic sequestration, dactylitis, and stroke. Furthermore, we also analyzed the haematological, biochemical and radiological parameters as well as use of antibiotics and exchange blood transfusion. Data were transcribed to Excel and later analyzed by IBM SPSS Ver23.
Results±13.7. Previous complications prior to death included acute chest syndrome in 66.3% cases, followed by stroke in 20.9%, hepatic sequestration in 6.9%, splenic sequestration in 3.5% and dactylitis in 2.3% cases. At the terminal event, patients presented with fever, cough and crepitation in 47%, 29% and 36% respectively, while abnormal pulse, blood pressure, respiratory rate and O2 saturation were seen in 55%, 64%, 46% and 55% respectively. Further abnormal chest x-ray, CT scan and abdominal ultrasound were seen in 57.5%, 88.5% and 50% respectively. Amongst the haematology parameters, there was a significant drop in the mean hemoglobin and platelet counts from baseline, whereas there was a significant rise in the WBC counts (p<0.05, student's t test). The biochemical parameters showed a significant rise in the LDH and CRP levels (p<0.05). All patients received antibiotics, 88% received blood transfusions, 35.7% received exchange transfusions, whereas 87.5% required NIV/ventilation. Finally, all patients presented with multi-organ terminal events that varied in the severity, but sepsis showed the commonest cause of death (54.3%).
Conclusion: Multi-organ failure was mostly associated with the terminal events relating to mortality. Although sepsis played a major role as a cause of death in association with multiorgan failure, low hemoglobin, and low platelet counts with increased WBC counts along with elevated LDH and CRP played a significant role in the terminal event in this cohort of SCD patients.

Disclosures
No relevant conflicts of interest to declare.