bluuebunny/crossref_metadata_2025_split huggingface dataset:
Busulfan Exposure Decrease CCyR Rate On Imatinib Therapy - Impact On Recent Pretreatment
Authors: Dyagil Irina , Lomaia Elza , Abdulkadirov Kudrat , Goryunova Elena , Lazorko Natalia , Romanova Ekaterina , Sbityakova Eugenia , Abdulkadirova Alla , Martinkevich Irina , Udalieva Vera , Usacheva Elena , Zotova Irina , Shuvaev Vasiliy , Machulaitene Elena , Poznyak Ekaterina , Ivanova Maria , Ilina Natalia , Koryagina Elena , Shneider Tatiana , Stepanova Svetlana , Dmitrenko Irina , Babkina Natalia , Perekhrestenko Tatiana , Masliak Zvenyslava , Zaritskey Andrey 
Published: October 2019

Abstract
Abstract 4452
Imatinib (IM) is now used world-wide as a first line chronic myeloid leukemia (CML) treatment. Although some time lack may exist between diagnosis and IM treatment.
Earlier (Blood 2009, 114: Abstract 4278) we have shown that in CML chronic phase (CP) pts with very long history of the disease(more than five years)the pretreatment by Busulfan was the adverse prognostic factor on Imatinib therapy.
Now we extend our study by a population of pts recently and for rather short time pretreated by busulfan.

Aim.
To investigate the effect of busulfan pretreatment on survival and responses to imatinib in CML pts in late CML CP.

Materials and methods.
In retrospective study 85 pts with CML CP from St-Petersburg, Leningrad region (Russian Federation) and several Ukrainian centers were included. The main inclusion criteria were: CML late CP (the duration of the disease more than 6 mos before IM start), IM therapy in routine clinical practice at least 12 months. The median time of IM therapy was 42,9 mos (12–97 mos), the median age of pts at the IM start was 49,5 years (19–83), male/female ratio 31/54.
23 patients were pretreated with busulfan (the study group) and 62 were not (control group). These groups were equal by age, sex, the median time from diagnosis to the IM start (28,3 mos in the study group and 23,9 in the control group), Sokal risk groups. Median time of busulfan pretreatment was 3,9 mos (1–62 mos). Statistical analysis was performed with SPSS 17.

Results.
In the whole group of patients frequency of complete cytogenetic response (CCyR) was 60% (51/85), estimated overall survival (OS) by 5 years from IM start was 87% (death rate 7% - 6/85). In the study group CCyR rate was significantly lower, than in the control group: 34,8% (8/23) and 69,35% (43/62), respectively, p=0,038. Estimated OS by 5 years was 72% (death rate 17% - 4/23) for busulfan-pretreated pts and 95% (death rate 3% - 2/62) for the control group, p<0,01.
Interestingly, that in the group of shortly busulfan-pretreated pts (the duration of pretreatment ≤6 mos), the lower CCyR rate has also been observed – 31% (4/13), although all other parameters were seemed equal to the control group (median time before IM start 28,3 mos).

Conclusion.
The pretreatment with busulfan impaired negatively the efficacy of imatinib treatment in CML late CP patients. Even short pretreatment (less than 6 mos) had adverse effect on CCyR. The mechanism is unclear. Busulfan pretreatment before imatinib therapy should not be used.

Disclosures:
No relevant conflicts of interest to declare.
Clinical Relevance of Pre- and Post-Transplantation Residual Disease, Hematogones and Natural Killer Cells in Adult Patients with Acute Leukemia
Authors: Li Chi-Cheng , Tang Jih-Luh , Lin Chien Ting , Ko Bor Sheng , Yao Ming , Loken Michael R. 
Published: October 2019

Abstract
Abstract 4490

Purpose
Allogeneic hematopoietic stem cell transplantation (allo-SCT) may rescue patients with acute myeloid and lymphoblastic leukemia (AML/ALL) even in high risk disease. Little has been investigated about prognostic impact of pre- and post-transplant residual disease (RD) status, hematogones (HG) level and natural killer (NK) cells level in the adult patients with acute leukemia.

Materials & Methods
We retrospectively studied 45 consecutive adult patients, including 31 AML and 14 ALL, receiving allo-SCT at National Taiwan University Hospital. Based on disease status at transplant, 18 patients were in standard risk; 16 in intermediate risk; and 11 in high risk disease. 28 patients underwent myeloablative conditioning and 17 received reduced-intensity SCT. Bone marrow samples were obtained both before conditioning therapy (pre-SCT) and at hemogram recovery after transplantation (post-SCT). RD, HG level and NK cells level were evaluated by multidimensional flow cytometry. Leukemia-free survival (LFS) was estimated by using Kaplan-Meier method.

Results
Pre-SCT RD-negative (RD-) was shown in 26 patients and RD-positive (RD+) in 19 patients; whereas post-SCT RD- was found in 39 patients and RD+ in 6 patients. Level of pre-SCT RD status ranges from 0–90% and level of post-SCT RD status ranges from 0–3%. Estimated one-year LFS were 71.8% in pre-SCT RD- compared to 0% in pre-SCT RD+ group (P=0.008, Fig. 1). In post-SCT flow cytometric analysis, one-year LFS were 33.2% in post-SCT RD- versus 25.0% in post-SCT RD+ group (P=0.002, Fig. 2). After combining pre- and post-SCT RD status, three groups of patients were identified; pre-SCT RD&minus;/post-SCT RD- (n=26), pre-SCT RD+/post-SCT RD- (n=13), and pre-SCT RD+/post-SCT RD+ (n=6). The classification further stratify the patients into different groups with distinct outcome (P=0.003, Fig. 3). We also found the median HG 0.2% (range 0–12%) and 0.1% (range 0–2.1%) and median NK cells 1.8% (range 0.2–20%) and 1.8% (0.02–15.5%) pre-SCT and post-SCT, respectively. The patients with higher NK cells, either pre-SCT or post-SCT, had longer LFS (P<0.001 and 0.004, continuous variables, respectively).

Conclusion
Our data suggest both pre- and post-SCT RD status and NK cells level could predict the transplant outcome. Further large-scale studies may be needed to confirm this point.

Disclosures:
No relevant conflicts of interest to declare.
Expression of CD56 in Acute Myeloid Leukemia (AML) Is Associated with Poor Outcome When Patients Treated with Stem Cell Transplant in Second Remission but Not in the First Remission
Authors: Chaudhri Naeem A. , Almhareb Fahed , Walter Claudia Ulrike , Nounou Randa , Khalil Salem , Bakshi Nasir , Owaidah Tarek , Al Zahrani Hazzaa , Mohamed Said , Rasheed Walid , Alsharif Fahad , Aljurf Mahmoud , Albitar Maher 
Published: October 2019

Abstract
Abstract 4880

Background:
The CD56 is a neural cell adhesion molecule (N-CAM) expressed in natural killer cells. CD56 expression on the surface of leukemic cells in acute myeloid leukemia (AML) has been reported to correlate with higher rate of relapse and to be associated with poor outcome when patients are treated with conventional intensive chemotherapy. The role of allogeneic hematopoietic stem cell transplantation (HSCT) in improving outcome in this subgroup of AML patients is not known. We investigated whether the outcome of CD56-positive AML patients differ from average AML patients when treated with allogeneic HSCT after intensive chemotherapy and its prognostic relevance in patients transplanted in the first (CR1) or second complete remission (CR2).

Methods:
Immunophenotyping data of 106 patients with AML who were treated with allogeneic HSCT was reviewed. The expression of the CD56 on the blast population as determined by flow cytometry was correlated with clinical data and outcome. The median age of patients was 24 (range: 14–57) and included 72 patients in the intermediate cytogenetic group and 30 in the adverse cytogenetic group. Of the 106 patients, 71 (67%) were treated with HSCT in their first remission (CR1) and the remaining patients were treated in CR2.

Results:
Twenty nine (28%) of all studied patients expressed CD56 on the surface of the blasts at diagnosis. When we consider only patients treated with HSCT in CR1, 17 (24%) were CD56 positive. The overall survival (OS) and event free survival (EFS) for patients who were positive for CD56 were not significantly different from the rest of the patients in the CR1 group. In contrast, in the group of patients who were treated with HSCT after relapsing (CR2), patients with CD56 positivity had significantly shorter OS (P=0.03) and DFS (P=0.006). In this group, 11 of the 35 (31%) were CD56+ and their median survival was 8.85 months while the median has not been reached in the CD56 negative patients.

Conclusion:
Our data suggests that the expression of CD56 in AML is a significant poor prognostic factor if patients are treated with HSCT after relapsing in their second remission. Although this should be confirmed in larger studies, the CD56 expression in AML should be considered as an adverse risk factor and favors treatment with allogeneic HSCT in the first remission and not after relapse in second remission. AML patients with CD56 positive blasts have higher incidence of relapse after chemotherapy and they might lose their opportunity of good outcome if HSCT is delayed and performed only in the second remission.

Disclosures:
No relevant conflicts of interest to declare.
Serum Free Light Chains Identify Patients With Monoclonal Gammopathy At Increased Risk Of Developing Renal Disease
Authors: Johnson Lawrence R. , Miller Gerald C. , Stout Spencer R. 
Published: October 2019

Abstract

Background
Monoclonal gammopathy (MG) is frequently associated with kidney disease (monoclonal gammopathy of renal significance; MGRS). International guidelines recommend the use of the serum free light chain (FLC) assay when screening for monoclonal gammopathies; an abnormal FLC ratio and an elevation of at least one FLC isotype indicates an Ig LC clone. However it is not known if, in patients with normal kidney function, the presence of a FLC clone predisposes to the future development of kidney disease.

Patients and Methods
A 22485 patient database with multiple laboratory tests and up to 15-year follow up (Regional Medical Laboratory, Tulsa, OK, USA) was analysed. There were 425 confirmed MG patients with no progression to multiple myeloma. Median age was 72 years (22-97 years) and M/F ratio was 177/248. FLC kappa and lambda were measured nephelometrically with Freelite® (The Binding Site Ltd, Birmingham, UK). Baseline was defined on the first available FLC measurement; this was available at inception in 258 (61%) patients and during follow-up in 167 (39%) patients. 128 patients with MG and an eGFR <60ml/min/1.75m2 and/or a clinical diagnosis of renal disease (ICD9 code) prior to and up to 100 days after baseline were excluded from the analysis. Statistical analyses, including Receiver Operating Characteristics (ROC) to identify monoclonal FLC (iFLC) cut-off were carried out using SPSS v21.

Results
297 (of 425) patients had a MG with normal renal function at baseline; 118 (40%) patients had an abnormal FLC ratio (88 kappa, median: 35.5 (7.7-2675) mg/L; 30 lambda, median: 83.6 (0.9-3552) mg/L). 21/297 (7%) patients developed renal impairment during the course of follow up (median: 852 (114-2388) days); 15/21 (71%) had monoclonal FLC production. In these patients there was no association between iFLC (median: 47.8 (0.9-3552) mg/L) and creatinine (median: 0.9 (0.5-1.5) mg/dL) levels (p=0.3966). Time to renal impairment (TTRI) was significantly shorter for patients with an abnormal v normal FLC ratio (75% TTRI: 1261 days v not reached (NR), hazard ratio (HR): 5.31; p<0.001). Age between groups was similar (median: 68 (22-97) v 72 (39-92) years; p=0.0544). In 118 patients withan abnormal FLC ratio, Cox regression analysis identified iFLC concentrations as being associated with the development of impaired renal function (p=0001). Furthermore, patients with iFLC>100mg/L (n=25) were at a significantly increased risk of developing renal impairment compared with patients with iFLC<100mg/L (n=93) (75% TTRI: 874 days v NR, respectively; HR: 6.10; p<0.001).

Conclusions
These results indicate that the presence of an Ig LC clone is associated with an increased risk of people with MG and normal kidney function progressing to renal disease.

Disclosures:
No relevant conflicts of interest to declare.
Role Of RECQ1 Helicase In Multiple Myeloma Biology and Drug Resistance
Authors: Viziteu Elena , Klein Bernard , Bruyer Angelique , Hose Dirk , Goldschmidt Hartmut , Grandmougin Camille , Basbous Jihane , Constantinou Angelos , Moreaux Jerome 
Published: October 2019

Abstract
Multiple Myeloma (MM) is a still lethal disease in 2013 characterized by the accumulation in the bone marrow of a clone of malignant plasma cells.
Recent studies have shown that epigenetic modifications play a role by silencing various cancer-related genes in MM. We initiated a microarray-based genome-wide screen for genes responding to DNMT inhibition in MM cells and built a “DNA methylation gene score” that makes it possible identification of myeloma patients that will be sensitive to DNMT inhibitors. Among the genes regulated by DNMT inhibitor and associated with the worst prognostic value in patients, RECQ1 was identified. RECQ helicase are DNA unwinding enzymes involved in the maintenance of chromosome stability. RECQ1 is highly expressed in various types of solid tumors. RECQ1 silencing in cancer cells results in mitotic catastrophe and prevents tumor growth in murine models. In glioblastoma cells, depletion of RECQ1 induces reduction in cellular proliferation, spontaneous γ-H2AX foci formation and hypersensitivity to drugs. Furthermore, it was described that RECQ1 protein could interact with MSH proteins, RAD51 and PARP1 involved in DNA repair pathways.
RECQ1 protein is expressed in human myeloma cell lines (HMCLs) and primary myeloma cells of patients. In four HMCLs (XG2, XG7, XG19 and LP1), RECQ1 was downregulated by conditional shRNA expression through lentiviral delivery. RECQ1 knock down inhibits growth of myeloma cells, induces 53BP1 foci formation and apoptosis. RECQ1 depletion sensitizes myeloma cells to DNA alkylating agent (melphalan) but not to corticosteroid (dexamethasone) or proteasome inhibitor (bortezomib). Using immunoprecipitation of myeloma cell nuclear proteins with anti-RECQ1 antibody, RECQ1 was shown to interact with PARP1 but not RAD51 or MSH2. An increased association of the two proteins was found upon DNA damages induced by melphalan. In agreement, RECQ1 depletion sensitizes myeloma cell lines to the PJ34 hydrochloride hydrate PARP inhibitor.
In conclusion, RECQ1 could represent a biomarker of drug resistance in MM, which is targeted by DNMT inhibitor. This suggests association of alkylating agents and/or PARP inhibitors with DNMT inhibitor may represent a promising therapeutic approach.

Disclosures:
Goldschmidt: Celgene and Janssen: Membership on an entity’s Board of Directors or advisory committees.
Anemia, Shortened Erythrocyte Lifespan and Stomatocytosis In a Flippase Mutant Mouse Strain
Authors: Lucy Coupland , Yabas Mehmet , Cromer Deborah , Winterberg Markus , Teoh Narcissus , Kirk Kiaran , Broer Stefan , Parish Christopher , Enders Anselm 
Published: October 2019

Abstract

Background
Mammalian erythrocytes are anucleate biconcave discs with marked flexibility and deformability, features necessary for efficient function. The cell membrane consists of a lipid bilayer containing proteins and an asymmetric distribution of phospholipids (PL). Phosphatidylcholine and sphingomyelin are predominantly concentrated in the outer layer and phosphatidylserine (PS) and phosphatidylethanolamine are mainly confined to the inner layer of the erythrocyte membrane. Maintenance of PL asymmetry is essential for erythrocyte survival and function as increased externalization of PS results in adherence of erythrocytes to vascular endothelium, activation of plasma blood clotting factors and premature removal from the circulation. Flippases, floppases and scramblases are the enzymes responsible for the establishment and maintenance of PL distribution.
A mouse deficient in the flippase ATP11C was generated through ENU mutagenesis and was found to have reduced hemoglobin in comparison to wild type (WT) littermates. This study was performed to characterize the etiology of anemia in these mice.

Results
ATP11C-deficient mice had significant reductions in erythrocyte numbers and hematocrit compared to WT but higher MCH and MCV. Reticulocyte numbers were comparable to WT as were serum iron parameters. Bone marrow and splenic erythropoiesis was normal in ATP11C mutant mice, however, erythrocyte lifespan was reduced by 35%. A marked increase in the frequency of PS+ erythrocytes was demonstrated in ATP11C mutant mice and was shown to increase with erythrocyte age. Bone marrow and splenic erythroblasts from ATP11C-deficient animals displayed a lower rate of PS translocation in vitro compared to WT confirming defective flippase activity.
Erythrocytes and late-stage splenic erythroblasts in ATP11C mutants were significantly larger than WT based on flow cytometry. SEM revealed the majority of mutant erythrocytes displayed stomatocyte-like morphology, as confirmed on peripheral blood smears. The osmotic fragility of the ATP11C-deficient erythrocytes was comparable to WT erythrocytes as was Na+ and K+ homeostasis.

Discussion
These studies reveal the important role of flippases in maintaining normal erythrocyte function through the maintenance of the asymmetric distribution of PS within the membrane. Perturbation of this process, as seen in the ATP11C-deficient mice, results in (i) increased exposure of PS on the erythrocyte outer membrane, (ii) increased size of late-stage erythroblasts and erythrocytes with stomatocyte formation (iii) reduced erythrocyte lifespan and (iv) normochromic anemia. This study, therefore, reveals a new mechanism for stomatocytosis and raises the question of whether mutations in ATP11C may serve as a previously unclassified cause of anemia in humans.

Disclosures:
No relevant conflicts of interest to declare.
Slit2N Inhibits Transmission Of HIV-1 From Dendritic Cells To T-Cells By Modulating Novel Cytoskeletal Elements
Authors: Shrivastava Ashutosh , Prasad Anil , Kuzontkoski Paula , Yu Jinlong , Groopman Jerome E. 
Published: October 2019

Abstract
During sexual contact, HIV-1 can enter the mucous membranes of the vagina, throat, or rectum. There, the virus encounters potential target cells, including antigen-presenting cells such as dermal dendritic cells (DC), Langerhans cells, and plasmacytoid DCs, which play pivotal roles in both innate and adaptive immunity. All DC subsets are susceptible to HIV-1 infection or internalization of intact virus, and appear to facilitate cell-mediated transmission of HIV-1 in the mucosa and lymphatic tissues.
Once internalized, HIV-1 can be transmitted from DCs to T-cells at a specialized junction termed the infectious synapse (IS). Recent studies reveal that several actin-rich DC membrane extensions, including actin filopodia, membrane sheets, cytonemes, and nanotubes, establish direct contact between cells at the IS and facilitate HIV-1 transmission. Although the virus can infect T-cells directly (cis-infection), transmission of HIV-1 from DCs to T-cells at IS (trans-infection and de novo trans-infection) appears to be some 10 to 100 times more efficient than direct infection; therefore, cell-to-cell transmission is an attractive target for novel HIV therapeutics.
We evaluated the effects of Slit2N, a ligand for the Roundabout (Robo) receptors, on the transmission of HIV-1 from DCs to T-cells. Slit2N inhibits HIV-1 transmission to T-cells and its replication. Binding of HIV-1 to DC-SIGN on the surface of DCs initiates signaling through cellular-Src (c-Src) and cell division control protein 42 (Cdc42), which modulates actin polymerization and filopodia formation via the actin-related protein 2/3 (Arp2/3) complex and mammalian Diaphanous 2 (mDia2). Slit2N inhibited HIV-1-induced signaling through both Arp2/3 and mDia2, decreased filopodial extensions on virus-infected DCs, and inhibited cell-to-cell transmission of HIV-1 at the IS in a Robo1-dependent manner. Of particular note, we identified Flightless-1 (Fli1) as a novel, Robo1-interacting protein, and demonstrated that it is required for efficient cell-to-cell transmission of HIV-1.
These results suggest that targeting the Slit/Robo pathway involves the modulation of previously unrecognized cytoskeletal elements in HIV-1 transmission, and thus, offers an innovative strategy to limit viral infection in the host.

Disclosures:
No relevant conflicts of interest to declare.
Biologic Response and Adverse Events To Stimate In Patients With Von Willebrand Disease
Authors: Song Xiangqian , Valentino Leonard A. , Simpson Mindy L. , Boggio Lisa 
Published: October 2019

Abstract
von Willebrand factor (VWF) is a large multimeric glycoprotein secreted from platelet α-granules and Weibel-Palade bodies of endothelial cells. VWF mediates the initial adhesion of platelets at sites of vascular injury and binds to and stabilizes blood coagulation factor VIII in the circulation to protect it from inactivation and clearance. von Willebrand disease (VWD) is the most common hereditary bleeding disorder and results from the deficiency or dysfunction of VWF leading to mucocutaneous bleeding, including epistaxis, menorrhagia, and excessive bleeding after trauma or surgery. Bleeding in patients with VWD is treated with infusion of plasma-derived VWF containing FVIII concentrates or 1-desamino-8-D-arginine vasopressin (DDAVP, desmopression). DDAVP is an analog of vasopressin antidiuretic hormone which can stimulate the exocytosis of VWF from storage sites and increase VWF and FVIII levels. DDAVP can be administrated by intravenous and intranasal routes. There are several reports of the safety and efficacy of intravenous DDAVP, but few with concentrated intranasal DDAVP (Stimate®). Here we report on the efficacy and safety of Stimate® in patients with VWD

Methods
Hospital records for 72 patients with VWD who received Stimate® from 1998 to 2012 were reviewed. The primary endpoint was the patients’ biological response to Stimate®, defined as at least a 3 fold increase compared to baseline of both ristocetin cofactor activity (VWF:RCo), factor VIII procoagulant activity (FVIII:C), or both VWF:RCo and FVIII:C are over 100% after Stimate®. Individuals not meeting the response criteria were deemed to be nonresponse. The adverse events were analyzed between different VWD types, response, age, gender, and race.

Result
Of those 72 VWD patients, 45 have type 1 (62%), 7 have type 2 (10%), and in 20 cases the subtype was unclear (28%). Responsive to Stimate® was observed in 43 (95.6%) of type 1, 4 (57.1%) of type 2, and 19 (95%) in which the diagnosis was unclear. In total, 16 patients (22.2%) had adverse events: 1 – allegoric response, 8 - mild headache, 4 - mild hyponatremia, and 4 - blood pressure (BP) reduced more than 20 mmHg.

Conclusion
Patients with VWD 1 have higher response rates to Stimate® than patients with VWD 2 in our test. The Stimate® is effective and safe for treatment of VWD.

Disclosures:
Valentino: Baxter, Bayer, Biogen Idec, GTC Biotherapeutics, Inspiration Biopharmaceuticals, Novo Nordisk: Consultancy, Membership on an entity’s Board of Directors or advisory committees.