bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of Spanish Experience During Imiglucerase Shortage
Authors: Giraldo Pilar , Irún Pilar , Alfonso Pilar , Dalmau Jaime , Fernández-Galán MAngeles , Figueredo Antonio , Ibañez Angela , Hernández-Rivas Jesús M , Luño Elisa , Marín-Jimenez Francisca , Martin-Nuñez Guillermo , Montserrat Jorge , De la Serna Javier , Villalon Lucia , Pocovi Miguel 
Published: October 2019

Abstract
Abstract 4725
In the last twenty years enzyme replacement therapy (ERT) with imiglucerase has been a clinically effective for Gaucher disease (GD). The recombinant glucocerebrosidase administered intravenously - usually at biweekly intervals by lifelong has improved the quality of life of patients, avoided spleen removal and bone complications. In the last months an acute shortage of imiglucerase manufactured by the Genzyme Corporation (MA, USA) has occurred as a result of viral contamination firstly and other deficiencies in the production facility. In September 2009 a position statement based on the findings of the European Working Group for Gaucher Disease and European Gaucher Alliance, established a set of key recommendations about identification and monitoring of at-risk patients threatened. In Spain the follow-up of patients and the strict complementation of rules of therapy have permitted to obtain a profile of the situation in a group of patients with restricted ERT. Patients and Methods: A total of 50 GD1 patients have been analyzed before and after 6 and 12 months of imiglucerase shortage. Have been excluded for analysis children in order to dose reduction has been minimal as well as patients who have switched to another ERT or miglustat therapy. Results: Gender: 25 males/25 females. Mean age of group: 45.3±15.3 (range:18-84) SSI at diagnosis(Dx): 8.7±3.8 (range:3-19) Chitotriosidase (CT) activity at Dx:13,383±12,783 nM/mL.h; CCL18/PARC at Dx: 767±1,198 ng/mL. 20% of patients were splenectomized and 78% had bone disease at Dx. During shortage 23 patients (46%) discontinued therapy, in this period only one patient suffered a bone crisis and other anaemia as complications. Mean reduction of haemoglobin level: 2.7% (NS), platelet counts: 5.4% (NS). CT activity was increased 135% (p<0.03) and CCL18/PARC 8.2% (p<0.08). In 17 patients (34%) imiglucerase was reduced at 50%, in this period seven patients (41.0%) suffered a bone pain and four patients (23.5%) required support therapy. Mean reduction of haemoglobin level 2.9% (NS), no changes in platelet counts. CT activity increase 48.2% (p<0.03) and not changes in CCL18/PARC concentration was observed. In addition in 3 patients (6%) the reduction was 75% and 7 patients (14%) switched to another ERT (4 patients) or miglustat (3 patients). Conclusions: In our experience, the shortage of imiglucerase in the last months has produced a incidence in bone pain of 20% and one case with anaemia and significant increase of CT activity and no significant changes in blood counts and CCL concentration, 14 % patients has required switch another therapy.

Disclosures:
Off Label Use: Lenalidomide is not approved for the treatment of smoldering multiple myeloma.
The Impact of Distance to Treatment Center on the Outcome of AML
Authors: Medeiros Bruno C. , Dunn Tamara J. , Kohrt Holbrook E , Coutre Steven , Gotlib Jason , Liedtke Michaela , Berube Caroline , Alizadeh Ash A. 
Published: October 2019

Abstract
Abstract 4742

Introduction
While the distance patients travel to a treatment center (DTC) adversely impacts survival of patients with trauma, cardiac, or neurological disorders, as well as certain solid tumors, less is known of its influence in acute myeloid leukemia (AML). Care for patients with AML involves frequent emergent and urgent management, often complicating primary therapy provided in distant tertiary referral centers. We therefore hypothesized that increased DTC has a negative impact on outcome. We tested this hypothesis by assessing the effect of DTC on survival of patients with AML receiving care at a single institution.

Patients and Methods
Within the Stanford Leukemia Database, we identified 884 consecutive adult patients between 1993 and 2009 meeting the following criteria: age >=18, newly diagnosed AML (excluding APL), clinical management at Stanford University Medical Center (SUMC), and verified residence location available for DTC determination. Of these, 571 were deemed fit by the admitting physician to receive myelosuppressive induction chemotherapy. DTC was calculated by straight-line journey distance between home address at the time of diagnosis and treatment center.

Results
The median age for the entire cohort is 55 years and 322 patients (36%) are older than 60 years of age. Median survival for the entire cohort was 14.0 months. DTC was not univariately associated with outcome as a continuous variable. When testing for a critical DTC threshold impacting outcomes across the entire cohort, we found a significant correlation between longer DTC and adverse outcomes, shorter DTC was associated with lower OS. Patients living within 20 miles of SUMC had a worse median overall survival (10.4 months versus 15.0 months, HR 1.23, corrected p-value 0.02). However, when adjusted for administration of induction chemotherapy (p<0.0001), age at presentation (p<0.0001) and karyotype at diagnosis (CBF vs other; p-value- 0.92), the negative impact of DTC was lost (p=0.08).

Conclusion
After accounting for confounding factors, DTC has no significant impact on the outcome of newly diagnosed AML patients receiving care at our institution. Unlike non-hematologic malignancies, distance to treatment center likely does not adversely influence outcomes for patients with AML.

Disclosures:
No relevant conflicts of interest to declare.
The Utility of the New Instrument for Comprehensive Symptom Profile Assessment In Patients with Multiple Myeloma
Authors: Novik Andrei A , Ionova Tatyana I , Kalyadina Svetlana A , Fedorenko Denis A , Mochkin Nikita E , Kurbatova Kira A , Nikitina Tatyana P , Gorodokin Gary I 
Published: October 2019

Abstract
Abstract 4757
Increased importance should be placed on the comprehensive symptom assessment in patients with multiple myeloma to accurately document the broad range of physical and psychological disease manifestations given from the patient perspective. The new developed symptom assessment tool - Comprehensive Symptom Profile in Multiple Myeloma Patients (CSP-MM) aims to provide an in-depth view of patient's problems. It is currently undergoing content validation through a structured, iterative process that conforms to the FDA industry guidance on the use of patient-reported outcome measures. We aimed to evaluate the utility of the new instrument providing evidence of its content validity.
Pilot sample of twenty two patients with different stages of multiple myeloma were included in this qualitative research study. Patients underwent either conventional chemotherapy or autologous stem cell transplantation. Mean age was 58 years old; male/female distribution –11/11. The CSP-MM is a self-reported tool which consists of 51numeric rating scales (where “0” - no symptom, “10” - most expressed symptom). Evidence of adequate tool content was collected from multiple sources: literature review, pilot CSP-MM completion, cognitive interviews with patients and clinicians, expert evaluation, and data quality control. Patients filled out the CSP-MM before and at different time-points of treatment.
The utility of the CSP-MM was demonstrated. After the completion of the pilot, patients were asked about their overall assessment of the questionnaire. Open-ended patient interviews provided a full understanding of the patient's perspective and showed that saturation of the items has been reached. The patients acknowledged the comprehensiveness of the tool. All of the items were easy for the patients to read and understand. Total number of completed surveys was 79 with only 1.6% missing items throughout all forms. Completion of the CSP-MM in paper and pencil format took 7–9 min. The data produced by the tool were clear for interpretation by physicians. According to the clinicians’ interviews, changes in symptom severity captured by the tool at different time-points of treatment gave the physicians information about patient experience and were used by them in day-to-day decision making.
Thus, the CSP-MM is an appropriate and practical tool to assess the symptom severity in myeloma patients. The utility of the questionnaire was shown. Pending further validation, the CSP-MM can be used to assess symptoms in MM patients and the patient benefit from the treatment.

Disclosures:
No relevant conflicts of interest to declare.
Methodological Issues In Modeling Hemophilia Treatment - What We Have Learnt In the Course of a Decade and What We Must Learn In the Decade to Come
Authors: Strandberg-Larsen Martin 
Published: October 2019

Abstract
Abstract 4762

Introduction:
The challenges faced by the hemophilia community because of economic constraints will increase in the future. Without disease specific pharmacoeconomic models to inform the decision process important decisions may be taken without taking hemophilia specific issues into account.

Objectives:
To investigate recent advances and current state-of-the-art knowledge in pharmacoeconomic modeling of hemophilia care we conducted a targeted literature review.

Methods:
Searches were conducted in MEDLINE®, and NHS Economic Evaluation Database using combinations of disease, and economic-related key words, limited to articles published in English between January 1970 and June 2010 (inclusive). A total of 127 articles (from 284 abstracts retrieved) were selected for detailed consideration.

Results:
Prior to the year 2000 the focus of the cost side of hemophilia treatment was not given much attention in the scientific literature. However in the last decade pharmacoeconomics have grown in importance and an increasing number of publications specific for this aspect of hemophilia reflect this trend. Still there is limited data on probabilities, costs and outcomes and remarkably few studies comparing QALY estimates of factor VIII prophylaxis in hemophilia. More studies are available specific for the limited inhibitor segment. Recommendations for reporting economic evaluations of hemophilia prophylaxis has been proposed and important ground clearing work has been published on theoretical aspects of hemophilia modeling.

Conclusion:
Economic analyses in hemophilia care are limited, but are increasingly in demand to examine the costs and outcomes associated with various treatment regimens. Unresolved questions critical to hemophilia remains such as the appropriate weighting of short term vs. future benefits and equity considerations associated with hemophilia being a rare genetic disease affecting children. Trials designed with pharmacoeconomic objectives in mind will be imperative. Data on generic and disease specific quality of life and resource use/cost data will provide whole new insights to how hemophilia impacts the lives of people living with this rare disease and will provide the data needed to assess the total value of different treatment regimens relevant for hemophilia.

Disclosures:
Strandberg-Larsen: Novo Nordisk A/S: Employment.
Urinary Tract Infection In Immunocompromised Children Under Chemotherapy
Authors: Shim Ye Jee , Lee Kun Soo , Ahn Hyo Seop , Hwang Tai Ju , Yoon Hwi-Joong 
Published: October 2019

Abstract
Abstract 4765

Purpose:
Infection is the most important cause of death in immunosuppressed cancer patients. And the urinary tract is a common source of infection in children. So we investigated the frequency of urinary tract infection (UTI) and the treatment outcome in children with cancer who were receiving antineoplastic therapy.

Methods:
We reviewed the medical records of children who were diagnosed as UTI during chemotherapy because of hematologic malignancies or solid tumors from January 2003 to July 2010 in Kyungpook National University Hospital. We defined as UTI when the patient showed high fever over 38.5°C and the single bacterial organism was cultured over 10,000/mL in urine sample using midstream urine collection technique. The bacterial strain, duration of fever, laboratory tests including urinalysis and gram stain, and imaging studies were demonstrated.

Results:
There were 63 cancer patients (male:female = 39:24) and 47 of them (74.6%, male:female = 30:17) experienced UTI during chemotherapy at least once. No one showed urinary symptom/sign like dysuria, frequency, urgency, flank pain or costo-vertebral angle tenderenss. The total episodes of UTI were 133 (male:female = 96:37) and the number of infection was mean 2.8 (1~10) per one patient. The common organism was Escherichia coli (25.6%), Enterococcus faecalis (15.0%), Klebsiella pneumoniae (10.5%), Enterococcus faecium (6.8%), Proteus mirabilis (6.8%) and Stenotrophomonas maltophilia (5.3%). Initial urinalysis was performed in 115 cases, but only 4 of them (3.5%) revealed pyuria. All gram stain results were negative. Duration of fever was mean 2.1 (1~6) days. The initial absolute neutrophil count (ANC) was average 1,930/μ L (0 ~ 12,610/μ L). The renal cortex scan using dimercaptosuccinic acid was performed for 43 cases to verify pyelonephritis. One showed decreased tracer uptake of upper pole of right kidney, and another 3 revealed diffuse decreased tracer uptake in both kidneys without specific photon defect. One episode of 3 was considered as urosepsis because the same organism (Klebsiella pneumoniae) was cultured from not only urine but also blood. The patient revealed hypotension and decreased renal function (glomerular filtration rate 41.4 mL/min). No mortality was observed.

Conclusion:
UTI is a very common infection in immunocompromised cancer children regardless of ANC which showed excellent prognosis with broad spectrum antibiotics. The bacterial strain was not different from that of immunocompetent children. But their symptom/sign was silent and the initial urinalysis and gram stain were not much help. So it is important to check urine culture for febrile cancer children under chemotherapy although the complication is very rare after UTI.

Disclosures:
No relevant conflicts of interest to declare.
Carbamazepine Is a Radioprotector and Radiation Damage Mitigator for Murine Hematopoietic Cell Line 32D Cl 3
Authors: Flickinger John , Shields Donna , Epperly Michael W , Zhang Xichen , Greenberger Joel S. 
Published: October 2019

Abstract
Abstract 4772
The search for new radiation mitigators includes targeted new- indication testing of known drugs. Carbamazepine (cbz) has been used for decades in the treatment of trigeminal neuralgia, epilepsy, mania and bipolar disorders, and has recently been demonstrated to reduce liver damage in a mouse model of alpha-1-antitrypsin deficiency by a mechanism that stimulates the proteasomal and autophagic pathway allowing degradation and clearing of abnormally folded antitrypsin. Because of its potential mitochondrial membrane ion channel effects, we tested cbz action on the irradiation survival of murine hematopoietic progenitor 32D cl 3 cells that were incubated for 1 hour in 1, 10 or 100 μ M cbz either before or after irradiation. Cells were irradiated to doses ranging from 0 to 8 Gy, plated in 4% methylcellulose, incubated for seven days at 37°C, and colonies of greater than 50 cells counted. Data was analyzed using linear quadratic or single-hit, multi-target models. Cbz added before irradiation resulted in radioprotection by an increased Do of 2.1 + 0.1 Gy (p = 0.0117), 2.3 + 0.1 Gy (p = 0.010), or 3.6 + 0.7 Gy (p = 0.0026) for 1, 10 or 100 μ M, respectively, compared to 1.5 + 0.1 Gy for control irradiated 32D cl 3 cells, with no significant change in the ñ (shoulder on the survival curve). Cbz added after irradiation mitigated against damage by an increase in the shoulder (ñ) on the survival curve with no significant change in the Do. Control irradiated 32D cl 3 cells had a ñ of 1.4 + 0.3 compared to 10.1 + 4.2 (p = 0.0113), 5.5 + 1.7 (p = 0.0185) or 3.6 + 0.8 (p = 0.0144) for cells treated after irradiation with 1, 10 or 100 μ M cbz, respectively. Cbz is known to stabilize ion channels in both cellular and mitochondrial membranes. Since irradiation induced apoptosis involves influx of calcium across the mitochondrial membrane followed by induction of nitric oxide synthase, nitric oxide and peroxynitrite formation, destabilization of the mitochondrial membrane and cytoplasmic release of cytochrome C; cbz-stabilization of mitochondrial ion channels may be the mechanism of this novel radiation mitigative effect of a commonly used drug.
Supported by NIAID grant U19AI068021.

Disclosures:
No relevant conflicts of interest to declare.
Characterization of Histone Modifications on Lineage-Affiliated Genes During Hematopoietic Stem Cell Differentiation
Authors: Fangping Chen , Tang Huarong 
Published: October 2019

Abstract
Abstract 4784
Hematopoietic stem cells (HSCs) are multipotent stem cells capable of self-renewal and multi-lineage differentiation. Though it has been shown that multiple factors take part in the maintenance of HSCs’ multipotency and differentiation potential, the mechanisms are unclear. Recent studies showed that histone modifications play an important role in maintenance of embryonic stem cells pluripotency and differentiation. To characterize the histone modification patterns of different lineages, HSCs were collected from umbilical cord blood and induced to differentiate to granulocytic, erythroid, and megakarytic in vitro. genes during HSC differentiation. Chromatin immunoprecipitation-quantitative PCR (ChIP-qPCR) technology was adopted to investigate the dynamic changes of histone modifications on lineage specific transcription factors and lineage–affiliated genes. Our results showed a certain level of H4 acetylation and H3 acetylation together with high level of H3K4me2 and low level of H3K4me3, H3K9me3 and H3K27me3 were present in lineage specific genes in CD34+CD38- HSCs. As CD34+CD38- cells differentiated, the modification level of acH3, acH4, H3K4me2, H3K9me3 and H3K27me3 on lineage specific genes remained the same, while H3K4me3 level increased greatly. In non-lineage specific genes, the acH3 and acH4 levels decreased, and H3K4me3 level remain at low level, while H3K9me3 and H3K27me3 levels increased. Thus, our data suggested that histone modifications played an important role in maintenaning the multipotency and differentiation capability of hematopoietic stem cells.

Disclosures:
No relevant conflicts of interest to declare.
Iinsulin Levels and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) May Explain a Possible Important Role of the Pancreas In Sickle Cell Disease Patients Outcome
Authors: Seixas Magda , Lopes Valma , Cezar Rodrigo , Carvalho Gildasio , Rocha Larissa , Lyra Isa , Reis Mitermayer , Goncalves Marilda 
Published: October 2019

Abstract
Abstract 4811
Sickle cell disease (SCD) is a hematological disorder characterized by the S hemoglobin homozygosis or the association with others variants of hemoglobin. The SCD is characterized by heterogeneous clinical outcome compound by hemolysis, chronic inflammation and vaso-oclusive and pain episodes. Red Blood cell (RBC) count, hemoglobin concentration (HB), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), total bilirrubin (BT) and indirect bilirrubin (BI) are important biomarkers in SCD patients follow-up. The insulin are essential for regulation and maintenance of glucose homeostasis and the insulin resistance are associated with chronic sub-clinical inflammation and inflammatory markers such as C - reactive protein (CRP) and white blood cells (WBC) count. These markers have been correlated with the severity of SCD. The aim of this study was investigate insulin levels and HOMA-IR in SCD and it correlation with important biomarkers. Here we developed a cross sectional study involving 40 SCD patients in the steady-state of disease aging 13.9+ 8.23 years old. The RBC and WBC count were carried out by automated method and the levels of BT, BI, AST, LDH and insulin levels were investigated by immunochemistry assay method. The mean of insulin levels was 3.2 ± 2.2 and HOMA-IR was 0.61 ± 0.46. SCD patients with insulin levels lowest than the mean had an increase levels of AST (p<0.001), BT (p=0.004), BI (p=0.008), LDH (p=0.005) and WBC count (p=0.005) and decrease of HB concentration (p=0.026), HOMA-RI (p=0.001) and RBC count (p=0.006). When we studied the 25th percentile a low insulin level was correlated with high ferritin concentration (p=0.019) and in 75th percentile high insulin levels were associated with high haptoglobin concentration (p=0.024), outside difference above described. Insulin levels were negatively associated with reticulocyte (p=0.0001, r= -0.5762; BT (p=0.0003, r= -0.5444), BI (p= 0.0017, r= -0.4856) and LDH (p=0.0018 r= -0.4833). In this study the HOMA-IR was used for evaluation of insulin resistance. HOMA-IR was negatively associated with WBC count (p=0.0039, r= -0.4465); reticulocyte count (p=0.0002, r= -0.5582); BT (p= 0.0012, r= -0.4885); BI (p=0.0101, r= -0.4074) e LDH (p=0.0094 r= -0.4108. Ours results demonstrate that levels of insulin and of HOMA-IR can be influenced by the oxidative stress and inflammation secondarily of the intravascular and extravascular hemolysis in sickle cell disease, suggesting an important role of these biomarkers in the disease pathogenesis. Additional studies are warranted to explain the contribution of the pancreas in the complex net of biomarkers alteration in the disease.

Disclosures:
No relevant conflicts of interest to declare.