bluuebunny/crossref_metadata_2025_split huggingface dataset:
Three-Month Cumulative Incidence of Thromboembolism and Bleeding After Periprocedural Anticoagulation Management of Patients with Active Cancer.
Authors: Tafur Alfonso J , Wolny Edyta , McBane Robert , Sutkowska Edyta , Slusser Joshua P , Hodge David O , Heit John A. , Wysokinski Waldemar E 
Published: October 2019

Abstract
Abstract 491

Introduction:
Chronically-anticoagulated patients with active cancer (Ca) often require temporary interruption of warfarin for an invasive diagnostic or therapeutic procedure. While such patients may be at increased risk for periprocedural thromboembolism and bleeding, there are virtually no estimates of these outcomes among Ca patients or the most appropriate periprocedural anticoagulation management. The aims of this study were to estimate rates of these outcomes among Ca patients and to test active cancer and “bridging” low molecular weight heparin (LMWH) as potential predictors of these outcomes.

Patients and Methods:
In a retrospective cohort study, all chronically-anticoagulated patients referred to the Mayo Clinic Thrombophilia Center for periprocedural anticoagulation management over the 11-year period, 1997-2007, were followed forward in time for the outcomes of venous and arterial thromboembolism (VTE; ATE), major bleeding and vital status within 3 months of consultation. Warfarin was stopped 4-5 days prior to the procedure and patients received bridging LMWH according to the estimated risk of thromboembolism and bleeding. All outcome events were centrally adjudicated using pre specified criteria.

Results:
The total cohort (n=2517) included 500 patients with Ca. Chronic anticoagulation indications included prior VTE (n=1033), mechanical heart valve (n=669), atrial fibrillation (n=530) and other (mainly vascular bypass; n=285). 65% and 64% of patients with and without Ca received bridging LMWH, respectively. Prior VTE was more common among Ca patients compared to those without CA, both in the bridged (56% vs 37%; p<0.001) and the non-bridged (48% vs 39%; p<0.05) groups. The 3 month rate for the composite of VTE, ATE or bleeding was higher among Ca patients compared to patients without Ca (5% vs 2%; p=0.004) due to higher post procedure rates of VTE (1% vs 0.2%; p<0.001) and major bleeding (4% vs 1.7%; p=0.009); the post procedure ATE rates were low in both groups (0.40% vs 0.45%). For the entire cohort, patients receiving bridging LMWH had a significantly higher rate of post procedure bleeding (5% vs 1%; p<0.05). Finally, there were significantly more deaths in Ca patients compared to non-Ca patients (5% vs. 1%; p<0.001).

Conclusions:
The three-month rates of VTE, major bleeding and death among patients with Ca in whom anticoagulation is temporarily interrupted for an invasive procedure is significantly higher than in patients without Ca, especially the major bleeding rate. Use of heparin increases this rate even farther, suggesting that bridging should be used with caution in patients with active cancer.

Disclosures:
No relevant conflicts of interest to declare.
GCS-100 Targets Apoptosis and Cell Cycle Regulation in Myeloma Cells.
Authors: Streetly Matthew , Maharaj Lenushka , Joel Simon P , Cotter Finbarr E 
Published: October 2019

Abstract
Abstract 4923

Introduction
Myeloma is characterised by abnormalities of multiple cellular pathways that result in apoptosis resistance, aberrant signalling and deregulated cell cycle. GCS-100 is a modified citrus pectin that has demonstrated galectin-3 inhibitory activity. It has recently been reported to have clinical activity against CLL (Cotter et al. ASCO 2009) and has previously been observed to have pre-clinical anti-myeloma effect even in the context of bortezomib resistance (Chauhan et al. Canc Res 2005). We have elucidated the mechanisms of action of GCS-100 in the context of myeloma cell biology.

Methods
The effects of GCS-100 on myeloma cell proliferation, cell cycle, apoptosis induction, cell death and cell signalling were examined in representative cell lines and primary myeloma cells. Cell viability assay, flow cytometric assessment of apoptosis, DNA content, mitchochondrial transmembrane potential and immunoblotting assessment of protein expression were assessed following GCS-100 exposure.

Results
Exposure of RPMI8226, U266 and OPM2 myeloma cell lines to GCS-100 confirmed that it inhibits proliferation and induces apoptosis with activation of both caspase-8 and -9 pathways. GCS-100 exposure was also associated with accumulation of cells in sub-G1 and G1 phases of cell cycle and a dose and time dependent loss of mitochondrial potential. Primary myeloma cells treated with GCS-100 had reduced viability both in isolation and in a stromal cell co-culture model. Examination of key anti-apoptotic and pro-apoptotic proteins revealed that Mcl-1 and Bcl-xL levels were reduced by GCS-100 and this was accompanied by a rapid induction of pro-apoptotic Noxa. Bcl-2, Bax, Bak, Bim, Bad, Bid and Puma remained unchanged. Pan-caspase inhibition abrogated Mcl-1 but not Bcl-XL reduction and inhibited loss of mitochondrial transmembrane potential. GCS-100 treatment also upregulated the cell cycle inhibitor p21Cip1 with concurrent reduction of the procycling proteins cyclin E2, cyclin D2 and CDK6. Furthermore, there was a reduction in signal transduction in the form of reduced activated IκBα, IKK and Akt as well as prevention of upregulated IκBα and Akt following stimulation with appropriate cytokines suggesting a potential microenvironment effect.

Conclusion
GCS-100 is a potent modifier of myeloma cell biology in a manner suitable for novel myeloma therapy.

Disclosures
No relevant conflicts of interest to declare.
Effects of Natural Compound EBSC-26 On Human Multiple Myeloma Cells.
Authors: Zhou Guangbiao , Liu Ying , Cheng Yongxian 
Published: October 2019

Abstract
Abstract 4924

Background
Human multiple myeloma (MM) is an incurable hematological malignancy at present, and screen for novel therapy remains an urgent need. The objective of this study was to assess the efficacy of natural compound EBSC-26 on multiple myeloma cells.

Methods
Inhibition of cell growth and proliferation of MM cell lines by compounds were assessed by WST-8 [2-(2-methoxy-4-nitrophenyl)-3-4-nitrophenyl)-5-(2,4- disulfophenyl)-2H-tetrazolium, monosodium salt] which allows sensitive colorimetric assays for the determination of the number of viable cells. Effects of compounds on cell cycle progression were analyzed by using flow cytometry. Apoptosis was evaluated by analysis of Annexin V. Microtubules were detected by immunofluorescence staining and confocal microscopy. Western blot and semi-quantitative/quantitative RT-PCR were performed to test protein/gene expression.

Results
EBSC-26 with a purity of up to 99.5%, was extracted from Centipeda minima (L.), a compositae plant used for the treatment of cold, nasal allergy, diarrhea, malaria, and asthma in China. We found that EBSC-26 suppressed proliferation/growth of U266, RPMI8226, dexamethasone-sensitive and resistant MM.1 cells, and induced apoptosis of these cells in a dose- and time-dependent manner. It synergized with Bortezomib and Doxorubicin in inhibition of MM cell proliferation. EBSC-26 overcame the protective effects of interleukin-6 and insulin-like growth factor-1 on multiple myeloma cells. It down-regulated interleukin-6-induced phosphorylation of STAT3 and insulin-like growth factor-1-induced phosphorylation of AKT. Moreover, EBSC-26 caused polymerization of microtubules, and induced G2/M arrest MM cells. Interestingly, an important G2/M-phase regulator, cyclin B1 was dramatically increased by EBSC-26 at protein level in a dose-dependent manner. EBSC-26 also decreased the phosphorylation of CDC2 at tyrosine 15.

Conclusions
These results suggest that EBSC-26 alone may have a potential in the treatment of multiple myeloma, and a combination of this agent with other compounds might provide further benefits.

Disclosures
No relevant conflicts of interest to declare.
Bortezomib, Doxorubicin and Dexamethasone (PAD) Combination Therapy for Chinese Relapsed or Refractory Multiple Myeloma.
Authors: Zhang Yongqing , Gao Guangxun , Wang Jishi , Chen Xiequn 
Published: October 2019

Abstract
Abstract 4948

Objective
To investigate the efficacy and safety of PAD (bortezomib, doxorubicin and dexamethasone) combination therapy for Chinese relapsed or refractory multiple myeloma (MM).

Methods
31 patients with relapsed or refractory MM received two to eight 21-days cycles of PAD: comprising an intravenous bolus of bortezomib 1.3 mg/m2 (P1,N=13) or 1.0 mg/m2 (P2,N=18) on days 1, 4, 8, and 11, doxorubicin 10mg per day on days 1 to 4, along with dexamethasone 40mg on days 1-4. Response to PAD was evaluated according to International Myeloma Working Group Criteria (IMWG 2006), toxicity was graded according to NCI CTCAE v3.0.

Results
25 patients (80.6%) achieved at least a partial response (PR), including complete response (CR) in 9 patients (29%), very good partial response (VGPR) in 7 patients (22.6%), PR in 9 patients (29%) and stable disease (SD) in 4 patients(12.9%), progression of disease (PD) in 2 patients (6.5%); median time to progression was 9.2 months, the median courses to achieve at least PR was 1.6(1-3) cycles, all of 7 patients with extramedullary plasmacytoma achieved at least PR after the first cycle of PAD, extramedullary plasmacytoma disappeared with 1-2 cycles of PAD. The efficacy was independent of traditional prognostic factors such asβ2-MG, Albumin,LDH and Hemoglobin which have previously influenced response to traditional chemotherapy. 1.5 year OS (Overall survival)of CR+VGPR group and PR group were 87.5% vs 46.7% (P=0.09). ≥PR response rate (CR +VGPR +PR) of P1AD and P2AD were 84.6% VS 77.8% (P= 0.501), CR+VGPR rate of P1AD and P2AD were 53.8% vs 50.0% (P=0.561 ). 1 year PFS(Progession-free survival) of P1AD and P2AD were 61.2% vs 55.6%(P=0.638), there were not difference between P1AD and P2AD in response rate(P= 0.501) and 1 year OS (P=0.872). Adverse events included thrombocytopenia in 15 patients ( 48.4% ), leukopenia in 8 patients(25.8%), peripheral neuropathy in 6 patients (19.4% ), varicella herpes zoster in 7 patients (22.6%), fatigue in 11 patients (35.5%) and diarrhea in 5 patients (16.1%), Thrombocytopenia and peripheral neuropathy of P1AD and P2AD were 46.2% vs 11.1%( P=0.037)and 53.8% vs 11.1%(P= 0.014).Common adverse reactions could be controlled with routine supportive treatmemt, one patient (3.2% ) died from respiratory failure during his fifth P1>AD.

Conclusions
PAD should be considered an appropriate treatment for Chinese relapsed or refractory MM, especially for MM with extramedullary plasmacytoma, its efficacy were independent of traditional prognosis factors, bortezomib dose reduction may reduce toxicities of PAD while retaining the efficacy.

Disclosures
No relevant conflicts of interest to declare.
Improved Overall Survival in Myeloma Patients Treated with Regimens Including Thalidomide/Revlimid/Velcade Vs Melphalan/Prednisone; a Retrospective Analysis.
Authors: Ashley Pandora , Holguin Mark , Song Juhee 
Published: October 2019

Abstract
Abstract 4961
A retrospective study was conducted to ascertain if the use of thalidomide, revlimid and or velcade was associated with improved survival compared to melphalan and prednisone or vincristine, adriamycin and dexamethasone (VAD). To avoid possible confounding issues of treatment with high dose chemotherapy and stem cell rescue, those patients were excluded from this analysis.
From 1997 to 2003, 98 patients diagnosed with myeloma and treated at Scott & White Memorial Hospital using non-transplant containing regimens were identified through the Scott & White Tumor Registry. Patients were divided into two groups based on treatment received. One group was treated with melphalan and prednisone or VAD chemotherapy (59 patients) and the second group was treated with regimens that included thalidomide, revlimid, or velcade (39 patients).
Median survival times were estimated for the entire cohort and each treatment group. Kaplan-Meier estimates of the survival by treatment received were estimated and log-rank test was performed to compare the survival distributions of the two treatment groups. Five year survivals of the 2 groups were compared using the Z test.
Median follow-up time for the entire cohort is 32.6 months (95% CI: 24.4-37.6) Median survivals are 38.7 months (95% CI 32.7-58.5) for the thalidomide/revlimid/velcade group and 24.4 months (95% CI: 14.4-35.7) for the melphalan and prednisone or VAD group. Five year Kaplan-Meier survival estimates are 0.3452 (95% CI: 0.2007-0.4945) for the thalidomide/revlimid/velcade group and 0.1325 (95% CI: 0.0593-0.2354) for the melphalan and prednisone or VAD group. The difference in survival between the two groups is statistically significant with p value of 0.0179.
In this retrospective analysis, treatment with newer agents such as thalidomide, revlimid or velcade is associated with a significant improvement in survival compared to melphalan and prednisone or VAD.

Disclosures
No relevant conflicts of interest to declare.
Continuous Administration of Low-Dose Cyclophosphamide and Prednisone as a Salvage Treatment for Multiple Myeloma.
Authors: Zhou Fan , Guo Lieping , Shi Haotian , Lin Chenhui , Hou Jian 
Published: October 2019

Abstract
Abstract 4962

Objective
To assess the efficacy and tolerability of continuous low-dose cyclophosphamide and prednisone regimen (CP) as a salvage therapy for multiple myeloma (MM).

Method
The CP regimen consisted of oral cyclophosphamide at 50 mg and prednisone at 15 mg daily. A total of 27 consecutive patients received the CP regimen: 19 patients had severe comorbid conditions; 8 were unwilling to continue conventional chemotherapy due to severe infection associated with conventional treatment. All patients had received 1-4 chemotherapeutic regimens prior to the current study.

Result
The overall response rate (complete remission, very good partial response, and partial response) was 66.7%. The median time to response was 2 months. In the patients who responded to the treatment, the median progression-free survival has not been reached. In the non-responding patients, the median progression-free survival was 4 months. In patients with severe comorbid conditions and unwilling to accept conventional chemotherapy because of severe infection, the physical conditions improved significantly.

Conclusion
Continuous low-dose CP regimen is an effective and well-tolerated salvage therapy for MM.

Disclosures
No relevant conflicts of interest to declare.
Modulation of Soluble Interleukin -2-Receptor (sIL2R) in Human Immunodeficiency Virus Myeloma (HIV-M) Patients Treated with Biaxin Pentoxifylline Dexamethasone (BPD).
Authors: McPherson Eugene , Patel Sanjay , Tassy P. 
Published: October 2019

Abstract
Abstract 4965
Soluble interleukin-2-receptor (sIL2R) is a T-cell derived cytokine that induce proliferation of activated T-cells, modulates macrophage function and phenotype and participates in differentiation of B cells. sIL2R levels reflect immune-system activation. and is elevated in HIV-M and may be used to predict esponse to therapy with immunomodulation therapy with BPD.sIL2R has been reported in several malignant diseases with correlation to disease activity. Proinflammatory cytokines IL-6, TNF-alpha, and IL-1b are positively correlated to sIL2R.Plasma cells may produce IL-6 by autocrine mechanism but a paracrine mechanism is involved in IL-6 production in bone marrow stromal cells. Growth of myeloma cells can be induced IL-6. We present a 43 YOF with HIV-M with elevated levels of sIL2R, C-reactive protein (CRP), IgG-kappa,lambda,IgM kappa level with serum free light chain
kappa/lambda ratio. Treatment with biaxin,pentoxifylline, and low dose dexamethasone for 12-24 weeks resulted in normal levels of sIL2R, CRP, IgG,IgM and serum free light chain ratios.

Conclusion
Modulation of sIL2R with BPD in HIV-M patients with elevated proinflammatory cytokines may arrest the disease proliferation by controlling the growth potential IL-6 in both bone marrow plasm cells and peripheral blood mononuclear cells and correlates with the duration of survival.

Disclosures
No relevant conflicts of interest to declare.
Hydroxyurea Effect On Marked Splenomegaly Associated with Primary Myelofibrosis: Response Rates and Correlation with JAK2V617F Allele Burden.
Authors: Siragusa Sergio , Vaidya Rakhee , Tefferi Ayalew 
Published: October 2019

Abstract
Abstract 4971

Background
Marked splenomegaly severely compromises quality of life in primary myelofibrosis (PMF). Preliminary results from the use of small molecule JAK2 inhibitors suggest prominent activity in reducing spleen size. In order to put such salutary effect of investigational drug therapy in context, it is important to determine the value of conventional therapy in this regard.

Methods
Study population was selected from the Mayo Clinic PMF database and consisted of patients treated with hydroxyurea (HU) as first-line therapy for symptomatic, marked splenomegaly (palpable at >10 cm below the left costal margin) and in whom follow-up information was available to assess response. Palpable spleen size measurements were recorded before and after 3, 6 and 12 months of HU therapy. Spleen response was defined as minimal (< 25% reduction), minor (25-50%), or major (>50%). Standard statistical procedures were used to correlate spleen response with other clinical and laboratory parameters, including cytogenetic and JAK2V617F mutational status.

Results
46 consecutive patients (median age, 62 years; range 38-75; 30 males) met the above stipulated eligibility criteria for study inclusion. Pre-treatment IPSS risk categories were low, intermediate-1 (int-1), int-2 and high in 4, 13, 10 and 19 patients, respectively; 7 patients were transfusion-dependent. Quantitative JAK2V617F and pre-treatment cytogenetic information were available in 25 and 36 patients, respectively; 15 (60%) patients were positive for JAK2V617F and mutant allele burden was > 50% in 6 patients; 17 (47%) patients carried either favorable (n=5) or unfavorable (n=12) cytogenetic abnormalities.
Overall response rate (major and minor) was 35% (16 of 46 patients) and major response rate 17%. Overall response rates were 10%, 67% and 33% in patients with undetectable JAK2V617F or mutant allele burden of < or ≥ 50%, respectively (p=0.04). Overall response rates in patients with normal, favorable and unfavorable karyotype were 32%, 40% and 33%, respectively (p=0.9). Response was not affected by age, sex, HU dose or pretreatment status regarding spleen size, IPSS score or transfusion need.

Conclusions
The current study provides background information on the value of conventional chemotherapy for controlling PMF-associated marked splenomegaly. The study also suggests a positive effect of JAK2V617F on treatment response to HU, a detail that needs to be considered when assessing the corresponding effect from a JAK2 inhibitor therapy.

Disclosures
Off Label Use: Hydroxyurea use in myelofibrosis.
The JAK2V617F Mutation but NOT Platelet Parameters Predict Thrombotic RISK IN Patients with Philadelphia-Negative MYELOPROLIFERATIVE Disorders (MPDs).
Authors: Wijayasinghe Deepti , Hart Stephen , Solkar Saida , McNamara Christopher j 
Published: October 2019

Abstract
Abstract 4984
Venous and arterial thromboses are important disease complications of both essential thrombocytopenia (ET) and polycythaemia vera (PV), the commonest MPDs. Predicting and managing this risk is not straightforward as the absolute platelet count does not necessarily correlate with thrombotic risk.
We retrospectively studied the platelet parameters, median platelet volume and platelet crit, in addition to the absolute platelet count using a Sysmex XE-2100 in patients with MPDs to determine if there was any relationship between these and subsequent thrombotic risk, as well as the JAK2V617F gene status. This has not been done previously.
There were 82 patients (25 PV, 33 ET, 13 chronic idiopathic myelofibrosis, 11 MPD unclassifiable) with a median age of 63 (range 37-94). Thromboses occurred in 32/82 patients (26 venous, 6 arterial) after follow up of 12-108 months. The JAK2V617F mutation was found in 77% of all patients. The median platelet count at diagnosis, prior to any therapy, of those patients who subsequently went on to experience a thrombotic event was not significantly different from those who did not: median platelet count 529 v 563 (p=0.06), median platelet volume 8.6 v 8.3 (p=0.36), platelet crit 0.49 v 0.5 (p=0.079).
Thrombosis was more likely to occur in those patients with a JAK2V617F mutation; thrombosis occurred in 43 % of JAK2V617F cases compared with 26% of cases without the mutation. The median platelet count in the JAK2V617F unmutated group was higher than in the group with the mutation (620 v 530 p=0.04); other platelet parameters in the two groups did not show any difference based on the presence of the mutation (median platelet volume 8.2 v 8.6 (p= 0.29), median platelet crit 0.52 v 0.5 (p=0.06)).
We conclude that platelet parameters, as assessed by a modern automated haematology analyser, do not predict for thrombotic risk in patients with newly diagnoses MPDs. Other factors such as platelet dysfunction, inherited thrombophilia and underlying vascular disease risk factors may be important. Our findings support the notion proposed by others that the presence of the JAK2V617F is a thrombotic risk factor.

Disclosures
No relevant conflicts of interest to declare.