bluuebunny/crossref_metadata_2025_split huggingface dataset:
A 5-Day Cytoreductive Chemotherapy Followed By Haplo-Identical HSCT (FA5-Bucy) As a Tumor-Ablative Regimen Improved the Survival of Patients with Advanced Hematological Malignancies
Authors: Yang Ting , Ren Jinhua , Lin Qiaoxian , Yuan Xiaohong , Luo Xiaofeng , Liu Tingbo , Zheng Xiaoyun , Chen Zhizhe , Hu Jianda 
Published: October 2019

Abstract
Background: Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) has been used when HLA-matched siblings are not available. Conditioning regimens aim to reduce tumor burden prior to HSCT and provide sufficient immunoablation.
Patients and Interventions: We report the outcome of haplo-HSCT in 63 consecutive patients (19 females/44 males) with high-risk or relapsed/refractory hematological malignancies (n=29-AML; 8-sAML; 19-ALL; 5-advanced-MDS; 2-CML-BC), followed at our Center from 2/2013 to 12/2015. Median age was 20 years (range: 1.1-49). Twenty-one patients achieved remission prior to transplant, while 42 did not (7%-98% BM blasts). No patient had severe infection or organ failure before HSCT. Patients received FA5-BUCY registered on http:// ClinicalTrials.gov (NCT02328950), i.e., 5-day salvage chemotherapy (Fludarabine/Ara-C) and conditioning (Busulfan/Cyclophosphamide). GvHD prophylaxis included ATG, CsA, MMF and short-term MTX.
Results: All patients received stem cells from bone marrow and peripheral blood, and achieved successful engraftment, except two who died before. With a median follow-up of 269 days (120-1081), 42/63 patients are still alive and disease-free. Two-year OS and RFS were similar in patients not in remission and in those in complete remission (61.3% vs 56.3%, p=0.88; 58.3% vs 56.3%, p=0.991). Non-relapse mortality and relapse incidence were 22.2% and 11.1%, respectively. Severe acute-GvHD occurred in 4/63 patients. Transplant-related mortality was low at day+100 (17.5%) and for the entire study period (20.6%). Unexpectedly, few patients experienced mild-to-moderate toxicity, and main causes of death were infection and GvHD. BM blast counts, age,and donor-recipient gender-pairs did not affect the outcome. Less chemotherapy cycles prior to HSCT might result in more favorable outcome.
Conclusions: Thus, haplo-HSCT with FA5-BUCY appears promising for advanced disease, especially when TBI and amsacrine, used for FLAMSA, are not available and in pediatric patients for whom TBI is not recommended.
Two-year OS and RFS in patients not in remission prior to HSCT compared to those in complete remission. The two-year OS and RFS in patients not in remission were similar to those from patients in complete remission (61.3% vs 56.3%, p=0.88; 58.3% vs 56.3%, p=0.991). Two-year OS and RFS in patients not in remission prior to HSCT compared to those in complete remission. / The two-year OS and RFS in patients not in remission were similar to those from patients in complete remission (61.3% vs 56.3%, p=0.88; 58.3% vs 56.3%, p=0.991).

Disclosures
No relevant conflicts of interest to declare.
Preclinical Characterization of TTI-281, a Novel, Orally Bioavailable BET Inhibitor: Predictive Biomarker Identification and Combination Treatment Analysis
Authors: Choi Jaehyun , Wang Chunlei , Wang Zezhou , Schimmer Aaron D. , Petrova Penka S. , Slassi Malik , Uger Robert A. 
Published: October 2019

Abstract
Small molecule inhibitors of the bromodomain and extraterminal domain (BET) proteins are being actively tested in clinical trials for many cancers, but patient selection strategies remain poorly defined. We have previously demonstrated TTI-281 is an efficacious BET inhibitor in multiple hematological malignancies models. Here, we present candidate biomarker genes that predict TTI-281 activity in vitro. Furthermore, we assessed the preclinical activity of TTI-281 in combination with 17 other drugs and found five compounds that improve TTI-281 potency.
We first determined the GI50 values for TTI-281 in 19 hematological cell lines. These GI50 values were then correlated with publicly available basal mRNA expression data for 58 candidate genes. Two novel candidates that predict the sensitivity of cancer cells to TTI-281 were identified: BCLAF1 (prediction accuracy: 83.3%) and HAPLN2 (prediction accuracy: 88.9%). Restricting the analysis to leukemia cells and including a third biomarker candidate gene (BCL2L1) improved the prediction accuracy to 100%.
Next, 17 drugs that are either approved or in development for the treatment of hematological malignancies were tested in combination with TTI-281. Five drugs were identified that significantly improved the potency (1.5-3.5 fold decrease in GI50) or maximum inhibitory effect (1.7-3.1 fold increase in maximum efficacy) of TTI-281 on multiple leukemia cells: azacitidine, everolimus, idelalisib, nilotinib, and vorinostat. However, the effects of combining TTI-281 with these five drugs were not observed in all hematological tumor cells, thus further studies are required to investigate the molecular mechanisms by which TTI-281 synergizes with other drugs.
In summary, the BET inhibitor TTI-281 is a promising anti-tumor agent with novel predictive biomarker candidates, capable of synergizing with azacitidine, everolimus, idelalisib, nilotinib, and vorinostat. Our preclinical data provide a strong rationale for further validating the current predictive biomarkers for TTI-281 in a clinical setting and probing the mechanism by which TTI-281 achieves synergy when combined with other anti-cancer agents.

Disclosures
Choi: Trillium Therapeutics: Employment. Wang:Trillium Therapeutics: Employment. Wang:Trillium Therapeutics: Employment, Patents & Royalties. Schimmer:Novartis: Honoraria. Petrova:Trillium Therapeutics Inc: Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Slassi:Trillium Therapeutics: Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Uger:Trillium Therapeutics: Employment, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.
Liposomal Delivery of a Phosphodiesterase 5 Inhibitor Enhances Prostacyclin-Mediated Adenosine Triphosphate Release from Human Red Blood Cells
Authors: Bowles Elizabeth , Sprague Randy , Ercal Nuran 
Published: October 2019

Abstract
Pulmonary arterial hypertension (PAH) is characterized by high pulmonary vascular resistance (PVR) and right heart failure. Red blood cells (RBCs) of PAH patients fail to release the vasodilator, adenosine triphosphate (ATP), when deformed as would occur when traversing the lung. Such a defect could contribute to increased PVR. However, RBCs of PAH patients do release ATP in response to prostacyclin (PGI2) analogs and this is augmented by phosphodiesterase 5 (PDE5) inhibitors. Current PAH treatment includes PGI2 analogs and PDE5 inhibitors alone or in combination. Unfortunately, these drugs can have untoward side effects. Encapsulation of drugs within liposomes (small lipid-membraned vesicles) that can be targeted to RBCs has been shown to increase effectiveness and tolerability of some medications.
The objective of this study was to determine if encapsulation of the PDE5 inhibitor zaprinast (ZAP) within liposomes is an effective means to deliver this class of drugs to human RBCs and if this approach would augment ATP release stimulated by the PGI2 analog UT-15c. Human RBCs were isolated and incubated with either blank liposomes (n=10), liposomes containing ZAP (n=9) or liposomes containing the PDE3 inhibitor, cilosatzol (CILO, n=10). RBCs (20% hematocrit) were then treated with UT-15c (1 µM). ATP release was measured before and 5, 10, and 15 min after the addition of UT-15c. In the presence of empty liposomes, the dose of UT-15c used did not stimulate ATP release. However, UT-15c did stimulate ATP release from RBCs pretreated with ZAP encapsulated by liposomes (P<0.01). The average time for maximal release was 9 ± 1 min. In contrast, when exposed to liposomes containing CILO, there was no ATP release following UT-15c administration.
These studies demonstrate that the selective delivery of a PDE5 inhibitor to human RBCs potentiates UT-15c induced ATP release. Moreover the findings are consistent with the hypothesis that directed delivery of this class of drugs to PAH RBCs could be a new and important method to augment PGI2 analog-induced ATP release from these cells. Such an approach could significantly limit side effects of both drugs without compromise of their therapeutic effectiveness in PAH.

Disclosures
No relevant conflicts of interest to declare.
A Prospective Study of Thyroid Function Status in Patients of Haemoglobin E Beta Thalassemia and Correlation with Serum Ferritin Level
Authors: Dolai Tuphan Kanti , Baul Shuvra Neel , Mandal Prakas Kumar , De Rajib , Chakrabarti Prantar 
Published: October 2019

Abstract
Introduction
Haemoglobin E-beta-thalassaemia (EBT) represent approximately 50 per cent of those affected with severe beta thalassemia.The highest frequencies are observed in India, Bangladesh and throughout Southeast Asia. Endocrinopathies are now amongst the common complications of thalassaemia and it is multifactorial in origin. Iron overload in EBT is also multifactorial. This study was undertaken to evaluate the thyroid dysfunction in patients of EBT and its correlation with serum ferritin levels.
Methods
EBT patients were evaluated prospectively to assess thyroid dysfunction status and correlate it with serum ferritin levels. High performance liquid chromatography was performed with Bio-rad beta thalassaemia short program variant II. Serum ferritin estimation was done with microplate immunoenzymometric assay and thyroid assay for TSH, free T4 and T3 were done by access 2 Immunoassay System, Beckman Coulter.
Results
50 patients with EBT were evaluated. The mean age of patients were 19.7 years (range: 12-47). There were 28 males and 22 females. There were 41(82%) and 9(18%) transfusion dependent and transfusion independent patients respectively and 40(80%) were on chelation therapy. In this cohort 22(44%) patients had thyroid dysfunction. Six (12%) and 16(32%) of patients were having hypothyroidism and subclinical hypothyroidism respectively. Mean ± Standard deviation (S.D) of serum ferritin level with hypothyroidism, subclinical hypothyroidism and euthyroidism was 1077 ± 371.8 ng/ml ,1422 ± 1361.0 ng/ml and 1252 ± 664.4 ng/ml respectively with correlation coefficient =0 [Fig 1 and Fig 2]. Serum ferritin levels do not predict thyroid dysfunction in patients of EBT. Male and female have equal preponderance for thyroid dysfunction. Patients with subclinical hypothyroidism were having few symptoms compared to frank hypothyroidism and majority of symptoms in either scenario were masked by thalassemia itself. Earlier age of onset of EBT is associated more with thyroid dysfunction however the association is not statistically significant (p=0.2). There was no association between spleen size and thyroid dysfunction (p=0.7).
Conclusions
Thyroid dysfunction was seen in 42% of EBT patients. Prevalence of hypothyroidism was found to be higher in EBT patients compared to general population but a definite correlation with the serum ferritin levels could not be established.
Figure 1 Mean serum ferritin level and thyroid status Figure 1. Mean serum ferritin level and thyroid status Figure 2 Correlation of serum TSH and ferritin level (correlation coefficient =0) Figure 2. Correlation of serum TSH and ferritin level (correlation coefficient =0)

Disclosures
No relevant conflicts of interest to declare.
Average Chronic Pain Medication Needed in Adult Patient with Sickle Cell Disease and Its Relation to Vitamin D Level
Authors: Master Samip , Patan Shajadi , Cingam Shashank , Shi Runhua , Mansour Richard Preston 
Published: October 2019

Abstract
Introduction: The chronic pain in sickle cell disease (SCD) arises from chronic bone damage as a consequence of bone marrow infraction during vaso-occulsive events. There are certain barriers to adequate pain management in adult patients with SCD, namely, limited knowledge among the clinicians, inadequate assessment, concerns about addiction, and biases against opioid use. We did retrospective analysis to investigate the average pain medication needed by adult patient with SCD. We also did analysis to see if there was a relation between plasma vitamin D level and amount of pain medication needed.
Methods:
We take care of approximately 300 active adult SCD at Hematology clinic at our institute. We did a retrospective analysis of 458 adult patients with SCD seen at our clinic between 2001 and 2016. We collected data on type of SCD, plasma 25 -hydroxyvitamin d level and amount of opioid pain medication in mg. To get uniform units of opiates, we converted all the different opiates into morphine.
Results:
The average morphine dose in a 24 hours period needed to manage chronic pain in an adult patient with SS type was 84 mg with standard deviation of 72, for SC type was 60 mg with standard deviation of 72 and for sickle beta thal type was 72 mg with standard deviation of 71. There were 4 patients with SS with hereditary persistence of hemoglobin F and average opiate dose in them was 84 mg.
We obtained vitamin d level on 223 patients and out of them, 47 had vitamin d level of <4.2 ng/ml (lowest level reportable by our lab). We also found negative correlation between amount of pain medication and vitamin D level. The spearman correlation coefficient was -0.2 and p value was <0.01.
Conclusion:
Because we were unable to find any previous reports of the correlation of vitamin D levels and opiate use in an adult population with SCD, we believe that this is the first study to report this correlation. It also provides a rough estimate regarding average amount of opiates that an adult patient with SCD needs. This correlation between Vitamin D levels and opiate requirement supports our current practice of screening all patients for Vitamin D deficiency using 25hydroxy vitamin D levels and treating all patients who are found to be deficient. We do not know if this Vitamin D replacement will reduce pain, bone health or the amount of opiate medication needed in the future.

Disclosures
No relevant conflicts of interest to declare.
Tumor Metastasis in VWF Deficient Mice: The Contributions of PGE2 and VEGF
Authors: Sosa Iberia Romina , Chava Kankana , Guillory Bobby , Cohen Daniel N 
Published: October 2019

Abstract
Dysregulation of the hemostatic system in malignancy leads to a hypercoagulable state and thrombotic complications. In addition to thrombosis, growing evidence from both human and animal studies, suggests that constituents of the hemostatic system also play an important role in tumor progression and metastasis. Platelets contribute to metastasis by protecting tumor cells from immune detection and inducing epithelial-mesenchymal transition, thereby facilitating the extravasation of circulating tumor cells out of the vasculature. Moreover, platelet-tumor cell interactions have been shown to promote prostaglandin E2 (PGE2) synthesis, an important modulator of angiogenesis and proliferation. The role of von willebrand factor (VWF) in malignancy has been of particular interest as it serves as an adhesive link between platelets and endothelium, and could possibly facilitate platelet interactions with tumor cells. Yet, the absence of VWF is associated with increased metastatic potential in a B16 melanoma mouse model, suggesting that the primary contribution of VWF to the metastatic model may not be platelet mediated. We employed a combined approach using cell lines and mouse models to explore the interaction of platelets and VWF in metastasis.
In vitro studies using lung and melanoma cells lines show that the interaction of resting and activated platelets with tumor cells leads to upregulation of COX-2 expression and PGE2 biosynthesis but does stimulate VEGF-A production. In an experimental metastasis model of C57BL/6 wild type and VWF null mice, the injection of B16 melanoma cells by tail vein yielded a significant increase in the number of pulmonary metastatic foci. PGE2 measurements from mouse serum showed reduced levels of prostaglandin in VWF deficient mice injected with tumor, suggesting that the absence of VWF precludes an important tumor cell-platelet interaction that facilities PGE2 production. Moreover, preliminary results show increased VEGF-A in VWF deficient mice, suggesting that increased metastasis in this model may be the result of dysregulated angiogenesis.
In conclusion, platelet-tumor cell interaction yield a pro-metastatic effect, in part mediated by PGE2 production. Despite its unique role in platelet adhesion and thrombus formation, VWF does not facilitate the interaction of platelets and tumor cells to produce PGE2. Its protective effect may lie in its ability to modulate angiogenesis via VEGF-specific pathways.

Disclosures
No relevant conflicts of interest to declare.
Dynamics of Hemorragic Events and Primary Hemostasis Deffects during Treatment with Ibrutinib. Real-Life Experience
Authors: Acedo Natalia , Loscertales Javier , Aguado Beatriz , Paz Yizel , Jimenez-Barral Elena , Arriero Alvaro , Alegre Adrian 
Published: October 2019

Abstract
INTRODUCTION: Ibrutinib is a first-in-class Bruton kinase inhibitor (BTK) registered for the treatment of Chronic Lymphocytic Leukemia (CLL), mantle cell linphoma (MCL) and Waldenström Macroglobulinemia (WM).
Increased risk of bleeding events is asociated with ibrutinib, mostly grade ≤2. Alleged mechanism for this risk could be the role of BTK in platelet activation via GPIb, GPVI and FVW.
We here present our experience regarding hemorragic events and hemostasis tests alterations in CLL patients (pts) treated with ibrutinib.
PATIENTS AND METHODS: 15 pts with relapsed CLL were started on ibrutinib between december/2012 and july/2016. Median age was 69 years (range: 42-83 years). 12 of them were male. Median exposure to the drug was 17 month (range 1- 38).
After 9 to 36 months from initiation of treatment (median 22 months) 6/15 were thouroughly interviewed about personal history of bleeding events and the following laboratory work was performed: factor VIII level, FVW antigen and activity, platelet function analysis (PFA-100TM) with ADP and epinephrine, and aggregation studies with colagen, ADP and arachidonic acid. Along these tests all patients had blood counts with platelets more than 100 x 10e9/L.
RESULTS: 3 out of 15 pts had bleeding events (grade 1 or 2), 2 consisting in spontaneus bruising and 1 in upper grastrointestinal bleeding, in the first weeks of treatment. 4 pts underwent minor invasive procedures with no complications, witholding the drug at least 3 days before and after. 2 pts were on concomitant antiplatelet (1) or anticoagulant (1, LMWH, due to AF) and had no bleeding events.
All pts tested (6/6) had normal or slightly elevated leves of F VIII, FVW:Ag and FVW:Ac. 2 pts had abnormal PFA-100TM and abnormal aggregations with any agonist. One case had normal PFA-100 TM while aggregations with colagen and AA were mildly altered.
COMMENTS: Our limited experience shows a moderate risk of minor bleedings consisting with a platelet disfunction drug-driven effect. Despite the fact that we have no baseline tests done, alterations in primary hemostasis test, including PFA-100TM and specially aggregometry could be expected early on after exposure to ibrutinib.

Disclosures
Loscertales: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Speakers Bureau. Alegre:Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.
Outcomes of Venous Thromboembolism (VTE) Treatment in Thrombocytopenic Leukemic Patients
Authors: Khan Maliha , Nassif Mohammed , Alzubaidi Mohanad , Cox Travis , Oo Thein H. , Garg Naveen , Rojas-Hernandez Cristhiam Mauricio 
Published: October 2019

Abstract
BACKGROUND
The current standard of care for the treatment of cancer-related VTE is low molecular heparin. Treatment of VTE in leukemia is complicated as patients suffer severe thrombocytopenia during the different phases of their malignant disease. The optimal treatment of cancer-related VTE in this population has still not been widely studied. Therefore, there is a dire need for research to provide evidence-based guidance on the optimal management of cancer related-VTE in leukemia population.
OBJECTIVES
The primary objective of the study was to estimate the recurrence rate of VTE (proximal lower extremity, pulmonary embolism or both) at 6 months from the institution of VTE-related treatment. Secondary objectives included overall survival, recurrent VTE event-free survival, and rate of complications attributed to therapies for VTE.
METHODS
A retrospective chart review of adult patients with thrombocytopenic leukemia patients who suffered VTE and were treated at MD Anderson Cancer Center between January 2002 and March 2016. Demographic, clinical, and VTE treatment-related data were collected. Primary and secondary outcomes were compared among the different VTE treatment-modalities using non-parametric methods. Kaplan-Meier curves were calculated and compared between the groups of VTE-treatment modalities using Log-Rank test. All comparisons were performed with a test significance of 0.05.
RESULTS:
At the time of abstract submission, a total of 101 patient-data have been analyzed. The most common type of leukemia was AML (2/3 of all cases). Study outcomes were compared between three groups: anticoagulation only, inferior vena cava filter only and no VTE-treatment intervention. We found no statistically significant differences in the demographic and clinical characteristics between the three groups, except for a lower median platelet count in the patients in whom no VTE-treatment intervention was performed (p<0.05). The VTE recurrence rate was low (<5%) and not different between the intervention groups. The median overall survival of the general population was poor (< 6 months) and significantly worse in patients who did not receive anticoagulation therapy for the management of VTE (p<0.01).
CONCLUSION:
Our study is the largest cohort reported to date on management of VTE in thrombocytopenic leukemia patients. Our preliminary data indicated that anticoagulation therapy and non-pharmacologic interventions for the management of VTE seemed to be safe and equivalent for the secondary prevention of recurrent VTE in that population. Future prospective cohort studies will likely confirm these findings.

Disclosures
No relevant conflicts of interest to declare.