bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Cost of Hospitalization for Thromboembolic Events in Patients with Colon or Lung Cancer
Authors: Borget Isabelle , Meyer Guy , Scotté Florian , Martelli Nicolas , Vainchtock Alexandre , Elalamy Ismail 
Published: October 2019

Abstract
Background: Venous Thromboembolic Event (VTE) is a common complication for cancer patients, leading to hospitalizations that increase the burden of cancer management. We evaluated the incidence and costs of VTE-related hospitalizations for patients with colon cancer (CC) or lung cancer (LC).
Methods: The French national hospital database (PMSI) was analyzed in order to identify patients whose colon cancer or lung cancer was diagnosed in 2010 and who were hospitalized for a VTE at least once during the following two years. The numbers of stays induced by a VTE, and the corresponding number of patients hospitalized, were determined using the disease-specific ICD-10 codes. Associated hospital costs were estimated from the perspective of the third-party payer, using the French official tariffs, on the 1,111 and 1,641 hospitalizations with VTE classified as primary or related diagnosis only (PD / RD) for colon and lung cancer patients, respectively.
Results: We identified 47,954 new patients with colon cancer and 39,454 new patients with lung cancer; in each group, 2,866 (6.0%) and 3,775 (9.6%), respectively, were hospitalized for a VTE or had a VTE during their hospital stay. During the 2 years of follow-up of these 6,641 patients, 1,707 (25.7%) were hospitalized for a VTE recurrence. In total, 4,104 stays for CC patients and 5,962 stays for LC patients were analyzed, including stays for recurrence.
In colon cancer patients, the mean cost per stay for a VTE classified as PD / RD amounted to 3,612 Euros and 3,457 Euros for first event and recurrence, respectively, and in lung cancer patients, to 3,674 Euros and 3,222 Euros for first event and recurrence, respectively. During the time of the study, mean hospitalization cost per patient who had at least one stay for recurrence was 5,441 Euros and 5,676 Euros in colon and lung cancer, respectively. Over a 2-year period, the total cost of hospital stays induced by VTEs classified as PD / RD reached 3.99 million Euros and 5.90 million Euros for colon and lung cancer, respectively, including a total amount of 1.49 million Euros for VTE recurrence.
Conclusion: In colon and lung cancer patients, VTE-related hospitalizations remain frequent and induce an elevated cost. This economic burden may be reduced by decreasing the occurrence of thromboembolic complications, using adequate prophylaxis and efficient management in this at-risk population.
Table: Cost of VTE-related hospital stays for patients with colon cancer or lung cancer 1st event Recurrence Global(1st event and recurrence) Colon cancer Mean cost/stay (Euros) 3,612 3,457 3,588 Total cost (Euros) 3,377,219 608,499 3,985,718 Lung cancer Mean cost/stay (Euros) 3,674 3,222 3,599 Total cost (Euros) 5,022,549 879,492 5,902,041

Disclosures
Borget: LEO Pharma: Honoraria. Meyer:LEO Pharma: Research Funding. Scotté:LEO Pharma: Honoraria. Martelli:LEO Pharma: Honoraria. Vainchtock:HEVA: Research Funding.
Acute Myeloid Leukemia-Derived Exosomes Transform Bone Marrow Niche into Leukemic Niche.
Authors: Kumar Bijender , Garcia Mayra , Weng Lihong , Lewis Xiaoman , Murakami Jodi , Hu Xingbin , McDonald Tinisha , DiGiusto David , Kumar Ashish , Bhatia Ravi , Chen Ching-Cheng 
Published: October 2019

Abstract
Increasing evidence suggests that leukemia cells take shelter in the bone marrow (BM) niche, where they hide from chemotherapy and continue to divide. As yet, how leukemia cells alter the BM niche to facilitate their growth and assist them in evading chemotherapy is unclear. In this study, we provide compelling evidences that acute myeloid leukemia (AML), through exosome secretion, transformed the BM niche to facilitate their own growth and suppress normal hematopoiesis.
Using AML xenograft and MLL-AF9 knock-in mouse model, we show that leukemia cells as well as AML-derived exosomes stimulate the growth of BM stromal progenitors and blocked the osteolineage development in our stromal compartment analysis. Histological analysis and micro-CT examination confirmed loss or thinning of the bone in both leukemia and leukemic exosome-treated animals. Expression of cell adhesion molecules (NCAM1, VCAM1, CD44, OPN & ICAM1) and factors important for angiogenesis (Angpt1, Angpt2 and VEGF) are upregulated, whereas genes important for HSC maintenance (CXCL12 and SCF), osteoblast (OCN, OSX, Notch3 and IGF1) and chondrocyte (ACAN, SOX9) development are suppressed.
While we observed increases in phenotypic LT-HSC in AML-derived exosomes treated mice, these mice show reduced multilineage reconstitution ability, increased cell cycle entry and higher sensitivity to myeloablative stress suggesting that HSCs from exosome-treated mice have lower stem cell activity than their counterparts from normal mice.In addition, leukemia-modified stroma cells exhibit marked reduction in ability to support normal HSCs. Pre-treatment of AML-derived exosome “prime” the animal for leukemia cell invasion and accelerate leukemia progression. Conversely,disruption of exosome secretion by targeting Rab27a in AML cells significantly delays leukemia progression. These data strongly support the notion that leukemia-modified niches favor leukemic cell proliferation and suppress normal hematopoiesis.

Disclosures
No relevant conflicts of interest to declare.
Tumor Suppressor Role of HIF-1alpha in Leukemia-Initiating Cells in Flt3-ITD-Induced Myeloproliferative Neoplasm
Authors: Velasco Talia , Cammenga Jörg 
Published: October 2019

Abstract
Hypoxia-induced signalling is a major regulator in normal and malignant hematopoiesis. The transcription factor HIF-1alpha plays a crucial role in the quiescence and self-renewal of hematopoietic stem cells as well as leukemia-initiating cells (LICs) of acute myeloid leukemia and chronic myeloid leukemia. Better understanding of the requirement of the molecular response to hypoxia in LICs could lead to new therapies targeting this pathway.
We have therefore investigated the effect of HIF-1alpha loss on the phenotype and biology of FLT3-ITD induced myeloproliferative neoplasm (MPN).
Using a combined transgenic mouse model (Mx1-Cre; Hif-1alphafl/fl; Flt3ITD/+) we showed that deletion of HIF-1alpha leads to a more severe MPN phenotype reflected by higher numbers of white blood cells and myeloid cells in peripheral blood, as well as a more severe splenomegaly. Loss of long-term hematopoietic stem cells (LT-HSCs: Lin- Sca1+ cKit+ CD48- CD150+) and increased number of lineage-restricted progenitors (Lin- Sca1+ cKit+ CD48+ CD150-) were the most pronounced effects on a cellular level upon the loss of HIF-1alpha. The proliferative effect of the HIF-1alpha loss was cell intrinsic and not at the expense of the ability of the LICs to self-renew because the disease was transplantable into secondary recipients recapitulating the same phenotype. Mice transplanted with FLT3-ITD induced MPN lacking HIF-1alpha succumbed to their disease (average survival of 35 weeks after transplant), while animals transplanted with MPN with wild-type HIF-1alpha suffered from MPN but did not die in the observation period of 60 weeks.
These findings are in contrary to what has been previously described for the role of HIF-1alpha in leukemia initiating cells and lead us to propose that HIF-1alpha could act as a tumor suppressor gene, inhibiting proliferation in myeloid malignancies. Our results provide evidence that targeting HIF-1alpha can lead to disease progression of MPN while not affecting self-renewal of LICs.

Disclosures
No relevant conflicts of interest to declare.
Pediatric Myelodysplastic Syndrome: Experience from a Single Center
Authors: Cetin Mualla , Unal Sule , Bayhan Turan , Aytac Selin , Kuskonmaz Baris , Tavil Betul , Uckan-Cetinkaya Duygu , Gumruk Fatma , Tuncer A. Murat 
Published: October 2019

Abstract
Pediatric myelodysplastic syndrome (MDS) is a group of heterogeneous clonal disorder with lesser frequency compared to adults. Additionally, there is much rare data in pediatric age group in relation to presentational findings and treatment.
The clinical and laboratory data, in addition to therapeutic interventions and outcomes of 47 patients in a single centre who were diagnosed between January 2001-May 2014 were summarized.
Median age of the study group was 2.8 years (0.1-16.8). The most common complaints at presentation included fever (27%), fatigue (17%), bleeding (15%), abdominal distention (13%), in addition to other rare presentational complaints including pallor, rash, vomiting, irritability, jaundice, stridor, abdominal pain and easy bruising. The underlying disorder was established as: neurofibromatosis in 5, Down syndrome in 3, secondary to prior chemotherapy in 2 (ALL and PNET), Fanconi anemia in 1, Jacobsen syndrome in 1, Klinefelter in 1. Final diagnosis was MDS in 22, JMML in 19, hypoplastic MDS in 4 and chemotherapy related MDS in 2. Median Hb, WBC, thrombocyte counts at presentation were 8.7 g/dl (4.1-12.7), 10.3x109/L (1.3-117) and 55x109/L (4-1515), respectively. Of the mutations studied related to MDS in 22 of the patients, k-ras positivity was the most common (23%). The most common cytogenetic abnormality was chromosome 7 related abnormalities (25%). Of the patients, 21 (45%) are alive and of these alive patients 62% are alive subsequent to hematopoietic stem cell transplantation.
The patients with pediatric MDS may present with various complaints and they may have underlying genetic diseases causing propensity for MDS. The survival is better among patients who underwent hematopoietic stem cell transplantation.

Disclosures
No relevant conflicts of interest to declare.
Comparison of IgA Heavy/Light Chain Immunoassays with Capillary Zone Electrophoresis and Total Immunoglobulin Measurements
Authors: Gartcheva Lidia , Petkova Violeta , Dimitrova Keranka , Petkova Veronika , Ganeva Penka , Guenova Margarita 
Published: October 2019

Abstract
Introduction: Capillary zone electrophoresis (CZE) and measurement of total immunoglobulins (total Ig) are standard techniques for the identification and quantification of monoclonal immunoglobulins (M-Ig). Heavy/light chain (HLC) pair analysis allows discrimination between Igκ and Igλ and as a result allows measurement of both the monoclonal involved and polyclonal uninvolved HLC pair. We compared measurement of M-Ig by CZE and total Ig to HLC levels.
Methods: 93 samples from 8 patients with IgA intact immunoglobulin multiple myeloma (MM) were analysed. M-Ig was measured using CZE Sebia Capillarys 2 system, total IgA (tIgA) and IgAκ and IgAλ HLC concentrations on a SPAPLUS analyser. IgA HLC levels were measured with Hevylite® and compared to published normal ranges (IgAκ (g/L): 0.57-2.08, IgAλ (g/L): 0.44-2.04, IgAκ/IgAλ: 0.78-1.94). Passing and Bablok fit analysis was used to determine correlation between the assays.
Results: Measurement of the involved HLC pair (iHLC) (median: 12.45g/L; range: 0.64-44.71g/L) compared well with CZE (n=34; median: 11.04g/L; range: 1.24-37.71g/L.; y= 1.2x + -2.65, R2= 0.94). Measurement of iHLC (median: 0.88. range: 0.05-21.55g/L) also compared well with tIgA measurement (n=65 median=1.44g/L; range: 0.227-21.11g/L, y=0.85x + -0.26, R2=0.98). Percent changes in iHLC concentrations from baseline through treatment compared well with CZE (n=28; y=1.59x + 0.15 R2=0.93) and tIgA (n=57; y=1.06x + 0.01, R2=0.96). Of the 34 samples with quantifiable M-protein by CZE, 32(94%) had an abnormal HLC ratio. The two discrepant samples were follow up samples from the same patient, where HLC normalised alongside total IgA entering the normal reference range. In addition, all 15 samples (15/65; 23%) where tIgA concentration was above the normal reference range all had abnormal HLC ratios. M-Ig was not detected by CZE in 48/82 (57%) samples, 46/48 of the samples (96%) had a normalised HLC ratio. In 38/65 (58%) samples, tIgA concentrations were within the normal reference range, and 34 (90%) had a normalised HLC ratio. HLC ratio for all patient samples normalised in subsequent samples following treatment.
Conclusion: The measurement of M-Ig is comparable between Hevylite® and both CZE and tIgA. The presented data indicate that Hevylite® is a more sensitive test for detecting residual disease and warrants prospective studies on larger cohorts of patients.
Acknowledgments:This work was partially supported by the National Science Fund (D02-35/2009).

Disclosures
Guenova: Novartis Pharma Sevices Bulgaria: Consultancy, Research Funding, Speakers Bureau; Roche Bulgaria: Consultancy, Research Funding, Speakers Bureau; Amgen Bulgaria: Consultancy, Research Funding, Speakers Bureau; Sanofi-Aventis Bulgaria: Consultancy, Research Funding, Speakers Bureau.
Evaluation of Anti-Neoplastic Effects of a New Hemostatic Agent Ankaferd Blood Stopper on Myeloma Cell Line and Plasmocytoma Development in Balb/c Mice: Results of the First in Vitro and in Vivo Study
Authors: Avcu Ferit , Guner Mustafa , Misirci Muammer , Elci Pinar , Safali Mukerrem , Goker Hakan , Haznedaroglu Ibrahim Celalettin 
Published: October 2019

Abstract
Ankaferd Blood Stopper (ABS), a unique traditional herbal mixture, has been used topically to stop bleeding for centuries in Anatolia. As well as ABS has been used as a blood-stopping agent, it may also have a considerable therapeutic benefit, because of its anti-infective, anti-neoplastic, and wound healing properties. The aim of this study is to investigate the anti-neoplastic effects of the ABS on myeloma cell line, in vitro and on the plasmocytoma development in Balb/c mice by intraperitoneal injection of pristane, in vivo. We therefore sought to evaluate the efficacy of ABS on MM cells and to study the modulation of cell-death pathways. The cytotoxicity of ABS against the MM cell lines (RPMI-8226, and ARH-77) was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide-dye reduction assay. Responses to ABS by RPMI-8226 and ARH-77 cell lines were dose dependent but not time dependent. The IC50 values for RPMI 8226 and ARH 77 myeloma cell lines in 24h were 12,84 μL/mL and 13,86 μL/mL, respectively. Various cell-death characteristics such as caspase-3, Bcl-2, Bax were studied in response to ABS, but we couldn’t demonstrate specific features of apoptotic cell death, in vitro. We have also investigated the effect of the ABS on the pristane (2.6.10.14-tetramethylpentadecane)-induced plasmacytoma (PCT) development on six-week-old BALB/c mice. Three groups of mice were treated with intraperitoneal ABS (1 mg/kg, 0.5mg/kg, and 0,1mg/kg) per-week for eight weeks after pristane-induced PCT development. The study was stopped at twelfth week, the remaining mice were autopsied, and peritoneal tissues were examined histologically for PCTs. A database of different groups’ mice was analyzed using Kaplan-Meier and Cox regression statistics based on variables. Kaplan-Meier analysis revealed a difference of the survival of pristane-induced alone between the groups of pristane-induced plus ABS 1 mg/kg, 0.5mg/kg, and 0.1mg/kg. (Log-rank, p=0.016; p<0.001 and p<0.001; respectively). The present results indicate that direct anti-tumor effect of ABS on pristane-induced PCT and significantly increased survival. This hypothesis needs to now be further investigated in clinical trials.

Disclosures
No relevant conflicts of interest to declare.
A Phase II Trial of Chloroquine in Combination with Bortezomib and Cyclophosphamide in Patients with Relapsed and Refractory Multiple Myeloma
Authors: Montanari Francesca , Lu Meina , Marcus Sara , Saran Ankeeta , Malankar Aditya , Mazumder Amitabha 
Published: October 2019

Abstract
Background: preclinical data suggest that autophagy can serve as an adaptive mechanism facilitating tumor cell survival and resistance to therapy-induced apoptosis. Subsequently, inhibitors of autophagy are thought to enhance the efficacy of therapeutic strategies designed to induce tumor cell apoptosis. Based upon our preclinical results, we hypothesized that the addition of chloroquine, an autophagy inhibitor, to the combination of a proteasome inhibitor, and cyclophosphamide might result in a synergistic effect.
Patients and Methods: We designed a phase II trial of bortezomib, cyclophosphamide and chloroquine in patients with refractory myeloma (defined by > 25% increase in M-protein) who progressed on a combination of bortezomib and cyclophosphamide. Treatment consisted of 42 day cycles repeated until disease progression with bortezomib 1.3 mg/m2 IV on days 1, 4, 8, 11, 22, 25, 29 and 32; cyclophosphamide 50 mg orally twice a day; and chloroquine at 500 mg orally daily on days 1-14 and 22-35. The primary endpoint was to estimate clinical benefit (CR+VGPR+PR+SD) after 2 cycles.
Results: Between October 2011 and April 2013, 11 patients including 7 men and 4 women were enrolled and treated. The median age was 62 years (range 53-80). All patients were ISS stage II and III. Prior therapies for most patients included transplant, bortezomib, cyclophosphamide and lenalidomide. One patient withdrew after C1D1 and two patients progressed prior to completion of cycle 1. Of the 8 evaluable patients who completed at least 2 cycles, 3/8 achieved a partial response, 1/8 showed stable disease and 4/8 progressed with a clinical benefit rate of 4/10 (40%). Among the 3 patients who achieved a partial response, median duration of response was 4 months (250, 131 and 117 days respectively). The most common non-hematological adverse events (AEs) observed in >25% of patients (any Gr/Gr >3) and felt to be at least possibly related to the study drug were: fatigue (91%/18%); constipation (72%); myalgia, nausea (64% each); cough (55%), diarrhea, neuropathy (45% each); congestion (36%/9%); anorexia and dyspnea (27% each). The most commonly observed hematological AEs were neutropenia (45%/36%) and thrombocytopenia (55%/45%). Data from LC3 and beclin1 assays used to measure correlations of clinical response with in vitro autophagy inhibition will be presented.
Conclusions: this study suggests that the addition of chloroquine to bortezomib and cyclophosphamide is effective in overcoming proteasome inhibitor resistance in a significant fraction of heavily pretreated patients, with an acceptable toxicity profile.

Disclosures
No relevant conflicts of interest to declare.
Synergistic Antitumor Effects of Chimeric Antigen Receptor-Modified T Cells and Oncolytic Virotherapy
Authors: Wang Xingbing , Gottschalk Stephen , Song Xiao-Tong 
Published: October 2019

Abstract
Oncolytic vaccinia virus (VV) therapy has shown promise in preclinical models and in clinical studies. However their use has been limited by constraints on delivery and effective tumor targeting. The combination of VV therapy with Chimeric Antigen Receptor-modified T cells (CAR-T cells) might overcome these limitations, since CAR-T cells can direct VV to the tumors. In our previous studies, we have developed a novel T-cell Engager Armed Vaccinia Virus (TEA-VVs) strategy that expresses secretory bispecific antibodies that bind both to CD3 and a tumor cell surface antigen EphA2. We demonstrated that EphA2-TEA-VV displays significantly enhanced antitumor activity by inducing bystander killing of tumor cells that are not infected with virus, compared to non-modified VV. In this study, we aimed to evaluate the efficacy of combination therapy of HER2-CAR-T cells with EphA2-TEA-VV. This combinational therapy should exerts its anti-tumor activity through three mechanisms: i) HER2-CAR-T cells recognize and lyse HER2-positive tumor cells, ii) VV infect, replicate in, and lyse tumor cells, and iii) bi-specific antibody expressed by EphA2-TEA-VV directs T cells to recognize EphA2 and kill tumor cells, overcoming tumor heterogeneity. In our preliminary studies, we demonstrated that EphA2-TEA-VV can effectively infect and replicated in HER2-CAR-T cells. In coculture assays, preinfectin of HER2-CAR-T cells with EphA2-TEA-VV resulted in strongly enhanced killing of HER2+EphA2+ A549 tumor cells. These results illustrate the potential of combining CAR-T cells and TEA-VV for synergistic effects that more effectively treat cancer.

Disclosures
No relevant conflicts of interest to declare.
Prevalence of Iron Deficiency and Iron Deficiency Anemia in Syrian Infants
Authors: Youssef Lama A , Albaroudi Issam N , Khodder Majed 
Published: October 2019

Abstract
Background: Iron deficiency (ID), with or without anemia, is the most common micronutrient malnutrition problem worldwide. Iron deficiency anemia (IDA) in infancy is linked to long-term motor and cognitive deficits. Infants and children in developing countries are particularly vulnerable to ID due to a negative iron balance resulting from increasing demands for growth that surpass dietary supplies. Recently, health reports have emerged on rising child malnutrition due to shortages of children’s foods and medicines in Syria. Nevertheless, factual data on prevalence are lacking.
Objective: To estimate the prevalence of ID and IDA in a cohort of non-displaced Syrian infants living in Damascus between November, 2011 and March, 2013.
Design/Methods: This was a prospective observational study conducted at the Children’s Hospital-based primary care clinic in Damascus. Information on type of feeding milk (maternal, iron-fortified formula or cow milk), and demographic characteristics was collected by face-to-face interviews with the parents of the study subjects. Hematological profile (complete blood count, reticulocytes and reticulocyte hemoglobin content (CHr)), and biochemical tests including serum ferritin and iron, and total iron-binding capacity were carried out. ID and IDA were diagnosed according to the 2010 American Academy of Pediatrics guidelines.
Results: Out of 155 infants assessed for eligibility, 135 infants met the inclusion criteria and were evaluated for iron deficiency. The average age was 12.4 ± 5.5 months (mean ± SD), and female to male ratio was 57:78. Only 31 (23%) of the study subjects were iron sufficient and not anemic, whereas 97 (72%) had ID, 75 (55.5%) had IDA, and 7 (5.2%) had non-iron deficiency anemia (thalassemia, hemolytic anemia, and macrocytic anemia). Prevalence of ID was statistically higher in males than females (85.33% vs. 62.26% respectively) (P=0.003). IDA was more prevalent in infants living in the countryside (76.25%) in comparison with their urban peers (53.84%) (p=0.04). Unexpectedly, ID and IDA were similarly prevalent regardless of the predominant type of milk fed to the infants (P >>0.05).
Conclusion: Our results unveil high prevalence of ID and IDA in Syrian infants between 2011 and 2013. Higher rates are expected in displaced infants and in remote regions of the country. These alarming findings call for immediate national and international collaborative efforts to provide iron supplementation and correct other existing malnutrition in Syrian children.

Disclosures
No relevant conflicts of interest to declare.