bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and Efficacy Of Abbreviated Induction With Only 4 Cycles Of Fludarabine (F), Cyclophosphamide (C) and Rituximab (R) In Physically Fit Patients With Chronic Lymphocytic Leukemia (CLL) Who Achieve Early Complete Remission (CR) With Undetectable Minimal Residual Disease (MDR)
Authors: Pavlovsky Carolina , Pavlovsky Astrid , Fernandez Isolda , Galeano Adriana , Lastiri Francisco , Pavlovsky Santiago 
Published: October 2019

Abstract

Background
Chemoimmunotherapy with 6 cycles of FCR is considered standard therapy for physically fit patients (pts) with Chronic Lymphocytic Leukemia (CLL). Many pts are unable to complete planned treatment, due to treatment related complications. Levels of minimal residual disease (MRD) have been shown to correlate with PFS in previously untreated patients with CLL (CLL8, Boettcher S et al. Leukemia, 2009). Achieving a negative MRD is therefore a mayor endpoint in treatment.

Patients and methods
From 4/2003, 39 physically fit pts with CLL who had IWCLL-NCI criteria for initiating treatment started therapy with FCR in our institution. Eleven pts had previously received chlorambucil/prednisone and 28 were not previously treated. Median age at start of therapy was 63 years (34-80), Binet´s clinical stage were A/B: 22 pts (56%) and C: 17 (44%). The CD38 expression was positive (>7% of cells) in 23 (59%) and negative in16 (41%) of the pts.
After 4 courses of FCR response was assessed in peripheral blood (PB) or bone marrow (BM) using three colour flow Cytometry. Negative MRD was defined as < 0,1% of light chain restricted CD5+CD19+ B cells in PB and BM as assesed collecting 100000 CD19 cells in a three colour cytometer (FacsScalibur- blue laser ). All these patients stopped therapy after evaluation due to early CR with eradication of MRD.

Results
All patients had negative MRD in peripheral blood, 35 were also evaluated in bone marrow, 29 showed CR and 6 nodular partial remission (NPR). Neutropenia and infectious events grade 3-4 were observed in 24% and 7% of all the courses respectively. No pts died of toxicity.
After a median follow-up of 81 months (4.6-120), progression free survival (PFS) and overall survival (OS) at 72 months was 51% and 75% respectively. Five pts died of progressive disease and 3 of a secondary neoplasm.

Conclusion
Stopping therapy in patients who achieve negative MRD after 4 cycles of FCR is safe and induces durable remission with a PFS and OS of 51% and 75% at 72 months exposing them to less chemotherapy. Large randomized trials are necessary to confirm this data.

Disclosures:
Pavlovsky: Novartis: Speakers Bureau; BMS: Speakers Bureau.
Feasibility Study Of a Randomized Control Trial To Evaluate An Internet-Based Self-Management Program For Adolescents With Hemophilia
Authors: Breakey Vicky R , Ignas Danial M , Warias Ashley , White Meghan , Blanchette Victor S. , Stinson Jennifer 
Published: October 2019

Abstract

Introduction
As adolescents with hemophilia approach adulthood, they must assume responsibility for their health and management of their disease. An online self-management program was developed to support adolescents during this transition.

Aim
To determine the feasibility of studying the online educational program using a non-blind, randomized control trial(RCT) design in terms of 1)Study accrual and attrition rates, 2) willingness to be randomized 3) compliance with the program and completion of the outcome measures, and 4) satisfaction with the program.

Methods
Adolescents, ages 13-18, were enrolled from three tertiary care centres in Canada in a pilot RCT (NCT01477437). After providing informed consent, adolescents were randomized to the intervention (8 week program with telephone coaching) or the control arm (no access, weekly telephone call as attention-strategy). Adolescents in both arms of the study were asked to complete pre- and post- outcome measures. Following completion of the program, quantitative analysis addressed the feasilibity measures and qualitative interviews were conducted to assess satisfaction.

Results
29 teens participated (intervention group, n=16, control group, n=13).Participants in the intervention arm spent an average of 50 minutes on the website per week completed the 8 modules in an average of 14 weeks (SD= 4.9). Among those randomized to the intervention, 2 participants dropped out of the study and 2 were lost to follow-up, resulting in an attrition rate of 25% (4/16). The control arm had a higher attrition rate of 54% (7/13) with 5 participants being lost to follow-up and 2 participants dropping out. For participants who completed the program, 17/18 (94%) completed the post-study outcome measures. Despite the study not being powered to assess efficacy, teens on the intervention arm showed significant improvement in disease-specific knowledge (p=0.004), self-efficacy (p=0.007) and transition preparedness (p=0.046) over time. There was a statistically significant improvement in the knowledge measure in the intervention group when compared to the control group (p=0.01). Overall, the teens found the website to be informative, comprehensive and easy to use and were satisfied with the program.

Conclusions
This feasibility study suggests benefit to the program and indicates a full scale RCT to be a reasonable next step with minor adjustments to the protocol. The higher than expected attrition rate in the control group, suggests the need to improve the strategies for maintaining participant engagement using a more active attention control group (static educational materials) in the design of this web-based intervention prior to a larger study to assess efficacy.

Disclosures:
Breakey: Baxter Bioscience: Research Funding.
Characteristics and Outcome Of Multiple Myeloma (MM) In African Americans (AA) Receiving Novel Agents and Autologous Stem Cell Transplantation (ASCT)
Authors: Bhatnagar Vishal , Wu Yin , Goloubeva Olga , Ruehle Kathleen , Milliron Todd , Yanovich Saul , Rapoport Aaron P. , Badros Ashraf 
Published: October 2019

Abstract

Background
African Americans (AAs) have a higher incidence of MM, about twice as much as Caucasians, and present at a younger age. Several studies have shown that presentation and outcomes of AA are similar to Caucasians treated with standard and high dose chemotherapy. The impact of induction with novel agents (IMIDs and proteosome inhibitors) and prognostic markers such as cytogenetics on different ethnic groups has not been fully evaluated.

Methods
We analyzed MM patients (AA=174 and Caucasians= 279) who underwent auto-SCT over fifteen years (1998-2013). Baseline characteristics are summarized in table below. Patients received induction therapy with standard chemotherapy (n=33) or dexamathesone (n=43) before 2001 or IMIDs or protesome inhibitors in addition to either chemotherapy (n=72) or dexamethasone (n=203) when treated after 2001. All patients received high-dose melphalan followed by auto-SCT. Response criteria were assessed according to the International Uniform Response criteria.

Results
AA were significantly younger but with no differences in disease stage or CRAB criteria at MM diagnosis with the exception of anemia. More AA women were referred and underwent auto-SCT relative to AA men. The subtype distribution was significantly different between AA and Caucasians (P <0.001). FISH and cytogenetics data for hyperdiploidy, hypodiploidy, deletions in chromosome 13q, 17p and 1p and IgH translocations were available for 271 patients. Approximately two-thirds of the patients had normal or favorable cytogenetics with more hyperdiploidy present in AA, although the population of patients with hyperdiploidy (43) is small for definitive conclusions. Response to induction was similar between AA and Caucasians, however response to novel agents plus dexamethasone was significantly better in Caucasians (p = 0.02). There was no difference in PFS between AA and Caucasians (median of 2.6 years; 95% CI: 2-3); In contrast, OS was significantly better in AA (median 7.7; 95% CI: 6.5-9.8) versus Caucasians (median 6.2; 95% CI: 5.5-7.5).

Conclusion
MM is heterogeneous disease. AA disease characteristics are different from Caucasians (subtype and cytogenetics). AA have inferior responses to novel agents, despite comparable and probably better survival to Caucasians, suggesting a favorable disease biology. Future studies focusing on AA patients are urgently needed to validate these observations prospectively.

Disclosures:
No relevant conflicts of interest to declare.
Peripherally Inserted Central Catheters Are a Good Option For Venous Access In The Patients With Hematologic Diseases
Authors: Takaiwa Naoko , Seki Masanori , Kurita Naoki , Yokoyama Yasuhisa , Sakata-Yanagimoto Mamiko , Obara Naoshi , Suzukawa Kazumi , Hasegawa Yuichi , Chiba Shigeru 
Published: October 2019

Abstract

Background
Central venous catheters are widely used for treatments of hematologic diseases. Conventional central venous catheters (CVC), however, often cause complications such as pneumothorax, hematoma, catheter-related blood stream infection (CR-BSI), and so on. Peripherally inserted central venous Catheters (PICC) are recently expected to reduce these complications. The aim of this study was to compare the frequencies of and risk factors for complications with PICC and CVC in patients with hematologic diseases.

Patients and Methods
We retrospectively reviewed all 363 patients who had inserted PICC or CVC for treatment of hematologic diseases in January 2011 through July 2013 at the University of Tsukuba Hospital. Overall and device-specific frequencies of infectious and non-infectious complications were evaluated and potential risk factors were captured.

Results
The PICC group (N = 215) and CVC group (N = 148) were similar in terms of clinical backgrounds, types of complications during catheter insertion, and total time of catheter-inserted periods. The CVC group had significantly higher proportions of patients who received hematopoietic cell transplantation (PICC 17.7% vs. CVC 49.3%, P<0.001). The significant intergroup differences were found in frequencies of CR-BSI (PICC, 1.4/1000 catheter days and CVC, 5.9/1000 catheter days; P<0.001) and local infection at the insertion site (PICC, 0.3/1000 catheter days and CVC, 2.3/1000 catheter days; P=0.002). The cumulative incidence of catheter removal for infective infectious complications was higher in the CVC group than the PICC group (PICC 8.7% vs. CVC 37.3%, P<0.001). Multivariate analysis showed that PICC significantly reduced the incidence of CR-BSI (odds ratio (OR), 0.15; 95% confidence interval (CI), 0.06-0.33; P<0.001). The incidence of CR-BSI was also significant higher in patients who received hematopoietic cell transplantation (OR, 2.4; 95%CI, 1.22-4.69; P=0.01). Phlebitis and deep vein thrombosis was noted in no patient in PICC group and 1 patient in CVC group.

Conclusion
Our date suggest that PICC is superior to CVC in terms of infectious complications. Low incidence of thrombophlebitis, observed in this study, is a key to a major change of practice from CVC to PICC.

Disclosures:
No relevant conflicts of interest to declare.
Determinants Of Cost Of Care For Persons With Severe Hemophilia
Authors: Evans Michael W. , Eyster M. Elaine , Hollenbeak Christopher S. 
Published: October 2019

Abstract

Background
The ability of a person with hemophilia to adhere to treatment recommendations aimed at preventing and controlling bleeding likely impacts clinical outcomes and resource utilization. Annual cost of replacement factor for persons with severe hemophilia on prophylaxis is estimated to be as high as $300,000 per year (Johnson KA and Zhou ZY. ASH Annual Meeting Educational Program. 2011; 413-418). Hemophilia care is optimized when delivered by a highly specialized hemophilia treatment center (HTC) (Soucie et al. Blood. 2000; 96: 437-442). Consolidation of care for persons with hemophilia from a large geographic region within an HTC results in demographic heterogeneity that may impact an individual's ability to adhere to treatment recommendations. Little is known regarding the impact of socio-demographic factors on treatment outcomes for persons with hemophilia. The purpose of this study was to identify disease-related, treatment-related and demographic variables that have a significant impact on morbidity and resource utilization.

Methods
We identified 69 persons with severe hemophilia treated at our HTC between June 2009 and June 2012. We collected data for the variables listed below in table 1. To assess morbidity and resource utilization, we collected data for total factor use, total outpatient cost, total inpatient cost, frequency of inpatient and outpatient encounters and length of stay when hospitalized. Risk factors were identified using linear regression. A subset analysis was performed to evaluate the impact of prophylaxis on patients without inhibitors. All statistical analyses were performed using STATA (version 12.0 College Station, TX). Statistical significance was defined as P < 0.05.

Results
Age and inhibitor status were the only variables to significantly impact cost in both inpatient and outpatient settings (Table 1). The statistically significant beneficial impact of prophylaxis was confirmed by subgroup analysis of patients without inhibitors with respect to number of hospitalizations and length of stay, but not total cost.

Conclusions
Identifying and addressing potential barriers to care will likely reduce morbidity and cost for persons with hemophilia. Caregiver status and age are demographic variables that may contribute to poor medical adherence resulting in increased morbidity and cost of care for persons with severe hemophilia.

Disclosures:
No relevant conflicts of interest to declare.
Exosome Mediated Wnt-Signaling Augments Side Population In Aggressive Lymphoma
Authors: Koch Raphael , Demant Martin , Aung Thiha , Guentsch Annemarie , Diering Nina , Chapuy Bjoern , Truemper Lorenz , Wulf Gerald 
Published: October 2019

Abstract

Introduction
Patients with aggressive B-cell lymphoma are treated in curative intention. However, some patients experience fatal relapse, originating from refractory lymphoma cells with the capacity for clonogenic regrowth. We here addressed repopulation capacity of lymphoma cell subpopulations and the mechanisms regulating the populational composition in the growing tumor.

Material & Methods
We identified side population (SP) cells in diffuse large B-cell lymphoma cell lines and patient samples with the DNA-binding dye Hoechst33342, analyzed clonogenicity in vitro and in vivo and screened for differentially expressed genes and DNA-methylation patterns. A GFP-containing lentiviral vector construct was used to keep track of side population cells cultured among mixed cultures of SP and nonSP cells. Manipulation of canonical wnt-signaling was performed by lentiviral sh-RNA constructs as well as pharmacological tankyrase-inhibition by XAV-939. In vitro data were supported by in vivo experiments using a chorioallantoic membrane-assay.

Results
Colony assays and suspension cultures of sorted SP and nonSP cells revealed restriction of clonogenic potential to the SP cell population as well as resurgence of nonSP cells from purified SP cell progenitors, while mixed culture assays using a GFP-vector construct tracing the SP vs. nonSP-population revealed homeostasis between the two populations, showing both SP and nonSP cells contributing to either cell compartment. SP cells show enhanced canonical wnt-signaling and increased exosomal secretion of wnt3a. Suppression of canonical wnt-signaling resulted in reduced clonogenicity. Exosome stimulation of DLBCL cell lines resulted in increased clonogenicity, stabilization of beta catenin and enhanced TOP/FOP activity.

Conclusion
Here we show that tumor cells reversibly switch between states of autonomous and non-autonomous clonogenicity, and that such transitions are regulated by exosome-mediated wnt signaling.

Disclosures:
No relevant conflicts of interest to declare.
Detection Of MYD88 L265P In Peripheral Blood Of Patients With Waldenström's Macroglobulinemia and IgM Monoclonal Gammopathy Of Undetermined Significance
Authors: Xu Lian , Hunter Zachary , Yang Guang , Zhou Yangsheng , Liu Xia , Cao Yang , Manning Robert , Patterson Christopher , Tripsas Christina K , Kanan Sandra , Chen Jiaji G , Lindeman Neil I , Treon Steven Peter 
Published: October 2019

Abstract
Waldenström's macroglobulinemia (WM) is characterized by bone marrow (BM) infiltration with lymphoplasmacytic cells and production of an IgM paraprotein. Lymphocytosis is uncommon in WM, and many patients exhibit peripheral B-cell lymphopenia. Recently, by whole genome sequencing, we identified a highly recurrent somatic mutation (L265P) in MYD88. Using real-time allele-specific polymerase chain reaction (AS-PCR), we demonstrated the presence of MYD88 L265P in 93% and 54% of patients with WM and IgM monoclonal gammopathy of undetermined significance (MGUS), respectively (Xu et al, Blood 2013).
To clarify the feasibility of using real-time AS-PCR assay to detect MYD88 L265P in peripheral blood, we first examined unselected mononuclear cells from peripheral blood (PB) samples of 88 patients with untreated WM. 81/88 (92%) of these patients were MYD88 L265P positive by bone marrow (BM) examination of CD19 selected B-cells; Of the 81 BM-MYD88 L265P positive patients, 32 (40%) demonstrated MYD88 L265P by AS-PCR in unselected PB mononuclear cells (PBMC) obtained at the time of BM examination. To enhance the ability to detect MYD88 L265P in PB samples, we next used AS-PCR in CD19 selected PBMC obtained from 198 WM patients which included untreated and previously treated patients. Among untreated patients, 106/118 (89.8%) were positive for MYD88 L265P in CD19 selected PB, whereas among previously treated patients, 55/80 (68.8%) were positive for MYD88 L265P (p=0.0002 vs. untreated). Simultaneously analyzed PB and BM samples from 65 untreated WM patients demonstrated positivity for MYD88 L265P in 58/65 (89.2%) and 55/65 (84.6%) of CD19 selected BM and PB samples, respectively. These findings yielded a sensitivity of 94.8%, specificity of 100%, positive and negative predictive values of 100% and 70%, respectively for AS-PCR testing of PB CD19+ cells for MYD88 L265P in untreated WM patients. In addition, we analyzed 12 untreated IgM MGUS patients with paired sampling of CD19 selected PB and BM cells. 6/12 (50%) IgM MGUS patients were positive for MYD88 L265P in BM CD19+ cells, with 5/6 (83%) of these positive patients demonstrating MYD88 L265P by AS-PCR in CD19 selected PB samples.
The overall results demonstrate a high concordance of MYD88 L265P status between PB and BM CD19 selected samples, particularly in untreated WM patients. The detection of MYD88 L265P by CD19 selected PB AS-PCR examination provides a convenient and less invasive method to support the diagnosis of WM and IgM MGUS.

Disclosures:
No relevant conflicts of interest to declare.
Epigenetic Silencing Of Mir-137 Contributes To The Proliferation Of Multiple Myeloma By Targeting AURKA
Authors: Qin Yu , Li Fei , An Gang , Hao Mu , Zang Meirong , Qiu Lugui 
Published: October 2019

Abstract

Background
MicroRNAs are non-coding small RNAs that modulate protein expression and are implicated in the pathogenesis of much kind of cancers. miR-137 was reported to act as a tumor suppressor in different cancers. In the present study, we describe the epigenetic regulation of miR-137 and its contribution in Multiple Myeloma (MM).

Methods and Results
Real-time RT-PCR was used to screen the expression levels of miR-137 in MM cell lines and CD138+ cell sorted from MM patients, which confirmed the downregulation of miR-137 in MM cell lines and patients, and the expression of cell lines increasing treated with epigenetic drugs 5-aza-dC. The methylation status of miR-137 CpG island was determined by bisulfite pyrosequencing and methylation specific polymerase chain reaction (MSP). Methylation of the miR-137 CpG island was frequently observed in MM cell lines and patients but not in healthy donor and MGUS. Cck-8 assay showed transfection of miR-137 precursor in MM cells significantly inhibited cell proliferation and increased cell drug sensitivity. Importantly, Ectopic expression of miR-137 in MM cells inhibited phosphorylation of mitogen-activated protein kinase (MAPK/ERK). To further identify miR-137 targets, we used bioinformatics analysis and confirmed using a luciferase reporter assay. To validate AURKA as miR-137 target, we cloned the 3' UTR sequence of human AURKA into the luciferase-expressing vector psiCHECK. 293Tcells were transiently transfected with this construct in the presence of pre-miR-137 or a scrambled oligonucleotide acting as a negative control. As reported in luciferase plate reader, miR-137 significantly reduced luciferase activity compared with the scrambled control miRNA. This indicated that miR-137 binds to the 3'UTR of AURKA and impairs its mRNA translation. Furthermore, NCI-H929 cells were transfected with AURKA shRNA vector psiHIV-mH1-AURK and westernblot showed phosphorylation of ERK was also significantly decreased.

Conclusion
miR-137 was epigenetic Silenced and targeted AURKA expression to contribute to the proliferation through MAPK/ERK pathway in MM.

Disclosures:
No relevant conflicts of interest to declare.