bluuebunny/crossref_metadata_2025_split huggingface dataset:
Critical Role of Histone Demethylase Jmjd3 in T Cell Migration
Authors: Fu Chuntang , Li Qingtian , Zou Jia , Xing Changsheng , Yin Bingnan , Lin Meng , Chu Junjun , Yu Jiaming , Wang Rongfu 
Published: October 2019

Abstract
Jmjd3, a histone H3K27 demethylase, is known to play a critical role in macrophage and T cell differentiation, but its role in T cell migration and T cell memory maintenance remains largely unknown. In this study, we show that Jmjd3 deficiency resulted in multiple alterations in T cell migration. Jmjd3 deletion limits CD4+ T cells egress out of the thymus, leading to thymic T-cell accumulation and peripheral lymphoid organ T-cell reduction. Gene profiling analysis of wild-type and Jmjd3-deficient CD4+ T cells identified altered expression of Jmjd3 target genes that correlated with changes in H3K27 and/or H3K4 trimethylation in promoters and gene body regions. The expression of the Jmjd3 target gene Pdlim4 is also regulated by Klf2, which regulates T-cell migration. Thus, our findings identify a novel Jmjd3 target gene, Pdlim4, in CD4+ T cell migration and provide insight into the molecular mechanisms by which Jmjd3 regulates T-cell migration.

Disclosures
No relevant conflicts of interest to declare.
Epigenetic Modifier Mutations in the LL-100 Panel
Authors: Quentmeier Hilmar , Pommerenke Claudia , Drexler Hans G. 
Published: October 2019

Abstract
The NCI-60 human cell line panel, developed for use in drug development comprises sixty human cancer cell lines derived from nine different tissues. Only six cell lines of the NCI-60 were derived from blood cancers. Therefore, most forms and subtypes of leukemia and lymphoma are not represented in the NCI-60 panel. To respond to this apparent gap, we suggest the novel LL-100 panel, 100 leukemia and lymphoma cell lines representing the major leukemia/lymphoma entities, for basic research and drug development.
Whole exome sequencing and RNA sequencing were performed to identify mutations in 100 cell lines. Here we list the 100 cell lines, ordered by subtype and show mutations in epigenetic modifier genes.
We found cell lines with mutations in ASXL1, EZH2, IDH1, TET2 and in DNMT3A. Hitherto, cell line OCI-AML3 was the only human cell line described with a DNMT3A mutation. Twenty-two percent of patients with acute myeloid leukemia contain DNMT3A mutations and the median overall survival with DNMT3A mutations is shorter than without. Most DNMT3A mutations are heterozygous and alter amino acid R882, R882H being the most common DNMT3A mutation in AML. Exogenously mutant murine R878H (equivalent to human R882H) inhibits DNMT3A activity in a dominant negative manner. We describe here that the AML cell line SET-2 carries a heterozygous G to A transition at chr2_25234373 (hg38) which leads to the DNMT3A R882H amino acid substitution. Chip-based methylation analysis revealed that the described DNMT3A targets IRF8, KLF2, HOXA11 and HOXB2 are hypomethylated in cell lines OCI-AML3 (DNMT3A R882C) and in SET-2 (DNMT3A R882H). These data suggest that SET-2 is a novel model cell line for functional analysis of the DNMT3A R882 mutation and a first gain in knowledge through data mining the LL-100 panel.

Disclosures
No relevant conflicts of interest to declare.
Economics of Multiple Myeloma
Authors: Wong Rachel , Tay Jason 
Published: October 2019

Abstract
Background
Multiple myeloma (MM) accounts for about 10% of hematologic malignancies, and the 5-year survival rate of patients diagnosed with multiple myeloma has increased by 14% over the past two decades with median survivals between 29-62 months. Improvements in survival has been attributable to improved therapeutics, representing a significant expenditure within the healthcare system. We seek to quantify the cost for caring for patients with MM from a third-party perspective.
Methods
We conducted a descriptive retrospective cohort costing study using administrative data from the Cancer Measurement Outcomes Research and Evaluations (C-MORE) at the Tom Baker Cancer Centre (TBCC). We identified incident cases of patients diagnosed with symptomatic multiple myeloma between 01 Jan 2002 and 31 Dec 2014. Demographic data were obtained together with their contact points with the healthcare system, including inpatient visits and lengths of stay, outpatient visits diagnostic and treatment visits, as well as medication usage. Using the Alberta Health Hospital Reciprocal Claim Guide and local pharmacy costs at TBCC, we assigned costs to health care utilization for incident cases of MM between our study period. Further, we stratified our data into 3 cohorts: 2002-2005, 2006-2010 and 2011-2014 to better appreciate secular trends.
Results
We identified 806 patients, but excluded 284 patients (35%) due to absence of data. The median duration of follow-up of the remaining cohort was 46 months (range 1-172). The median number of lines of therapy is 2 (range 1-8) with 32% overall enrolled in at least one clinical study. Table 1 details the cohort demographics with an overall survival (OS) of cohort of 55% (median survival of 81 months, 95% CI=68-94). The average cost of care per patient per year is $49,077, with $30,895, $46,333, $69,627 for Cohorts 1, 2 and 3 respectively. Chemotherapy (not including clinical trial medications) costs represents the largest cost-item.
Conclusions
Our study suggests that the survival of patients with MM diagnosed at the TBCC has improved consistent with the literature, but with an increasing cost of care. Despite incomplete administrative data from C-MORE, the current available data could help support health care Administrators better prioritize health care resources.
Table 1. Table 1.

Disclosures
No relevant conflicts of interest to declare.
Atypical Chronic Myeloid Leukemia
Authors: Ashangari Chandralekha , Tumula Praveen K. 
Published: October 2019

Abstract
Introduction: Atypical chronic myeloid leukemia (aCML), BCR-ABL1 negative is a rare myelodysplastic syndromes (MDS)/myeloproliferative neoplasm (MPN) for which no current standard of care exists. We present one of the rare presentations of aCML in an elderly patient.
Case: A 76 year old male presented to the Hematology clinic for consultation after discharge from local hospital for elevated WBC count. Past medical history was significant for COPD, acid reflux, peripheral arterial disease and hypertension. Physical exam was unremarkable. Initial labs were significant for leukocytosis of 30 k/cu mm, anemia with Hb 10 gm/dl, thrombocytosis 695,000 with neutrophilia of ANC 25,200. Peripheral blood was negative for JAK2 V617F and BCR-ABL. Peripheral blood flow cytometry showed granulocytic left shift with 1.5% myeloblasts. Bone marrow biopsy suggestive of hypercellular marrow (100%) with myeloid predominance, atypical megakaryocytes, increased ring sideroblasts (49% of NRBC), increased blasts (5%) and dysgranulopoeisis over all suggestive of Myelodyplastic Syndrome/Chronic Myeloproliferative Disorder (MDS/MPD). Cytogenetics were positive for U2AF1 positive, CSF3R T6181, CSF3R Q776 pathognomonicof atypical CML and negative for BCR-ABL, FLT3. He was considered transplant ineligible. He was started on Azacitadine and is currently receiving 2nd cycle therapy. He is also receiving darbepoeitin periodically to avoid frequent transfusions. He is currently transfusion independent.
Discussion: Increased WBC count (e.g., cutoffs of >40×109/L or 50×109/L), increased percentage of peripheral blood myeloid precursors, female sex, and older age are adverse prognostic factors for overall survival or leukemia-free survival in aCML. aCML cases lack in Philadelphia chromosome. Overall 50-65% of patients show cytogenetic abnormalities. The most frequent is +8 (25%). Other changes such as -7 and del(12p) have also been recurrently observed. Patients with aCML have an estimated median survival between 14 and 30 months. aCML tends to exhibit a more aggressive clinical course than other MDS/MPN subtypes.
Figure. Figure.

Disclosures
No relevant conflicts of interest to declare.
Safety of Autologous Stem Cell Transplantation in Patients with Known HTLV-1 Infection: A Case Series of 4 Patients
Authors: Gupta Vishal K , White Paul , Sanchorawala Vaishali , Quillen Karen , Sarosiek Shayna , Brauneis Dina , Sloan John Mark 
Published: October 2019

Abstract
Human T-cell lymphotrophic virus types 1 and 2 (HTLV-1/2) are delta retroviruses endemic to the Caribbean and Japan (Gessain et al., 2013). They are known to cause adult T-cell lymphoma-leukemia (ATLL) and tropical spastic paraparesis/HTLV-1 associated myelopathy (HAM) (Mahieux et al., 2003). Given the link between immunosuppressive states and development of lymphoproliferative disorders, there is hesitation on the behalf of clinicians to offer stem cell transplantation to patients who test positive for HTLV-1/2 antibody. We reviewed four cases of patients who underwent autologous stem cell transplantation (ASCT) at our institution after having tested positive for HTLV-1/2 antibody (Table 1). The median patient age at the time of ASCT was 58 years (range, 51-60). Two patients tested positive for HTLV-1 antibody and two tested positive for HTLV-2 antibody. Two patients underwent ASCT for treatment of multiple myeloma, one for diffuse large B-cell lymphoma (DLBCL), and one for light chain amyloidosis (AL). The myeloma patients received standard induction therapy with cyclophosphamide, bortezomib, and dexamethasone (CyBorD) or lenalidomide, bortezomib, and dexamethasone (RVD). The DLBCL patient received rituximab, ifosfamide, carboplatin, and etoposide (R-ICE), while the AL patient underwent ASCT without induction. Three patients underwent conditioning with high-dose melphalan (200 mg/m2; HDM) and the lymphoma patient received carmustine, cyclophosphamide, and etoposide (BCV). Median stem cell collection was 8.35 x 106 CD34+ cells per kg (range, 4.8 -30.7). The median follow-up for these patients from date of transplantation was 22.4 months (range, 7.3-38.6). Median time to neutrophil and platelet engraftment was 9.5 days (range, 8-10) and 10 days (range, 9-14) respectively. Among these four patients, none developed complications related to HTLV-1/2 infection during the follow-up period. Two patients had a post-transplant course complicated by febrile neutropenia, and one patient developed typhlitis. One patient died on day + 221 due to a recurrence of cholangiocarcinoma leading to liver failure, and the other three remained alive at the time of last follow-up. Our data provides support that testing positive for HTLV-1/2 does not preclude eligibility for ASCT.

Disclosures
Sloan: Stemline Therapeutics: Consultancy.
The Appropriateness of Fresh Frozen Plasma (FFP) Administration in the Community Teaching Hospital
Authors: Shikdar Sufana , Ghionni Nicholas , Green Eric , Hommadov Kakageldi 
Published: October 2019

Abstract
Objective: Studies demonstrated that inappropriate usage of fresh frozen plasma (FFP) is associated with adverse reaction and poor health outcome in the hospitalized patients. Reducing inappropriate FFP administration in the inpatient settings can minimize potential for adverse events, and foster controllable cost expenditure. Guideline regarding indication of FFP transfusion is scarce. We aimed to assess the appropriateness of FFP transfusion in the setting of community teaching hospital.
Methods: A retrospective chart review of patients received FFP transfusion in two community teaching hospitals between 2016-2017 were included in our study. Frequency of appropriateness of FFP transfusion was reported. We also reported percent increase from previous years to compare the FFP usage from 2010-2011 to 2016-2017.
Results: Of 138 patients received FFP transfusion in 2016-2017, 62% (86 patients) received inappropriate transfusion. 18% of patients received FFP to correct high INR (>1.6) requiring emergency surgery. 53% of the patients received inappropriate transfusion for bleeding in 2016-2017 compared to 25% in 2010-2011. There was 10% rise of inappropriate or overuse of FFP transfusion in 2016-2017 than 2010-2011.
Conclusion: Inappropriate FFP transfusion is significantly associated with adverse health outcome and increased healthcare cost. This study justifies the need for continuous audit for appropriate use of FFP.

Disclosures
No relevant conflicts of interest to declare.
Single Institutional Experience with Nivolumab in Relapsed/Refractory Classic Hodgkin
Authors: Dada Reyad , Malas Al-Beirouti Bassim T. , Zabai Yazeed 
Published: October 2019

Abstract
Objectives : One of the newly discovered mechanisms to escape the immune response in classic Hodgkin lymphoma (cHL) is to induce immune tolerance through interaction of program cell death 1 (PD-1) on activated T cells and PD ligand-1 (PD-L1) on tumor cells. Tissue of patients with cHL was recently found to overexpress PD-L1. Nivolumab is a novel checkpoint inhibitor designed to block PD-1 and inhibits interaction between PD-1 and PD-L1. Unlike many available antibodies and chemotherapies, nivolumab itself is not cytotoxic but rather inhibits the tolerance of tumor cells through activation of the immune system.
Patients and methods: We report on ten patients with relapsed/refractory cHL who were treated between 05/2016 and 03/2018 with single agent nivolumab in a tertiary care hospital. Follow-up was performed after 4 cycles with positron emission tomography (PET). Patients' files were retrospectively analyzed.
Results:
Mean age was 26.2 year (range 15-40). Prior to nivolumab 3/10 and 5/10 patients failed ASCT and brentuximab vedotin respectively. Mean follow-up time was 12.3 months (range 5-32). Average of prior lines was 6.3. After 4 cycles of nivolumab response rate was 80% with complete metabolic (CR) and partial remission rates of 70% and 10% respectively. In one case PET showed stable disease and another patient experienced progressive disease. Three deaths occurred after 5, 9 and 32 months of nivolumab's initiation.
One patients experienced pneumonitis grade 2 which was manageable by oral steroids. Another patient had an asymptomatic TSH elevation. Two patients had grade 2 neutropenia. No serious adverse events (grade ≥3) were observed. All patients experienced a remarkable improvement of quality of life. On treatment start, two patients had performance status ECOG 3 and 4 which were attributed to refractory Hodgkin lymphoma. They recovered dramatically each to ECOG 2 within 7 days and 10 days after nivolumab start respectively.
Conclusion: The CR rate seen in our cohort supports the high sensitivity of relapsed/refractory cHL to checkpoint inhibition seen in Checkmate 205. Nivolumab induces impressive clinical and radiological responses with excellent tolerance. The drug enriches our treatments armamentarium in treating cHL. Further controlled studies are needed to determine the effectiveness on a large patients' cohort and its role in earlier lines.

Disclosures
No relevant conflicts of interest to declare.
A New Cellular Immunotherapy for the Treatment of Multiple Myeloma without Development of Graft-Versus-Host Disease
Authors: Firer Michael A , Yado Sofi , Galia Luboshits , Or Reuven 
Published: October 2019

Abstract
Multiple myeloma (MM) is a malignant plasma cell disorder that accounts for approximately 10% of all hematological cancers. Despite recent advances, long-term survival is rare after autologous bone marrow transplantation (auto-BMT) and/or treatment with recently introduced anti-myeloma agents and disease recurs in virtually all patients. Allogeneic bone marrow transplantation (allo-BMT) is an effective treatment that can provide partial or complete remission in patients with MM. The therapeutic potential of allo-BMT is attributed to the "graft-versus-myeloma" (GvM) effect that aims to destroy residual tumor cells that survived an induction protocol of chemotherapy/radiotherapy and to maintain immune surveillance to prevent relapse. However, allo-BMT remains a controversial treatment, since the donor T cells that mediate the GvM effect are also the source of the cells that react to other tissue alloantigens and induce graft versus-host disease (GvHD), a major cause of morbidity and mortality in allo-BMT recipients. Nonetheless, allo-BMT remains the only potentially curable treatment for MM. Recently TCR Vβ CDR3-size spectratype analyses in an animal model of MM identified T cells subfamilies involved in the anti-host and anti-tumor reactivity. We have now carried this work further and tested the potential of integrating auto-BMT with a donor lymphocyte infusion (DLI) composed only of anti-MM reactive Vβ 2, 3 and 8.3 T cell subfamilies. The results demonstrate that these T cell subsets are indeed involved in the generation of a potent GvM response in MM bearing mice and is associated with enhanced survival. Importantly, the GvM response was not accompanied by the development of GvHD. Nonetheless, the GvM response was not sufficient to completely inhibit relapse. We then pre-stimulated donor T cells with MM cells in vitro in the presence of co-stimulatory factors and found that our selective DLI protocol induced a vigorous and long-lasting GvM which translated into long-term survival, again in the complete absence of GvHD. Interestingly, quite similar results were obtained by treating MM-bearing mice with repeat doses of naïve donor Vβ 2, 3 and 8.3 T cell subfamilies. The treated mice showed significantly lower serum paraprotein levels and myeloma infiltration in bone marrow and spleen. Taken together, the results suggest that a transplantation protocol involving only tumor cell-reactive donor T cell subfamilies might be devised for MM patients that results in a potent GvM with enhanced survival but without symptoms of GvHD.

Disclosures
No relevant conflicts of interest to declare.
The Experience of Postpartum Bleeding in Women with Inherited Bleeding Disorders
Authors: Vandermeulen Heather , Petrucci Jessica , Floros Georgina , Dainty Katie , Sholzberg Michelle 
Published: October 2019

Abstract
Introduction and Objective: Women with inherited bleeding disorders have a maternal mortality rate nearly ten times higher than women without bleeding disorders. To date, the postpartum bleeding these women experience has not been well studied. Postpartum hemorrhage (PPH) affects 6% of all deliveries and is the leading cause of maternal death worldwide (19.7%). The incidence of PPH in women with inherited bleeding disorders is greater than unaffected women however estimates of relative risk are highly variable. In this high-risk population, we set out to explore the experience with, understanding of and attitudes regarding postpartum bleeding.
Materials and Methods: This qualitative study involved focused interviews of women with inherited bleeding disorders about postpartum bleeding. Women followed at a multidisciplinary clinic for women with inherited bleeding disorders who have experienced childbirth within the last 5 years were included in the study. The interview style was semi-structured and questions were designed in collaboration with a qualitative methodologist. Interviews continued until the point of saturation of themes. All interviews were transcribed and then analyzed using qualitative descriptive analysis.
Results: We interviewed ten women with inherited bleeding disorders. Saturation of themes occurred after six interviews. Themes that emerged include normalization of excessive bleeding, difficulty distinguishing normal from abnormal postpartum bleeding and empowerment of women by having a clear delivery care plan. Although these women felt generally prepared for immediate postpartum bleeding, there was less awareness regarding delayed postpartum hemorrhage.
Conclusion: To our knowledge this is the first study to assess the experience of postpartum bleeding in women with inherited bleeding disorders. Our analysis shows that these women become desensitized to heavy vaginal bleeding. As a result, excessive postpartum bleeding was not recognized by many of the women we interviewed. We also highlight the importance of a multidisciplinary delivery care plan for these women. We have identified key areas for targeted intervention for these patients and their healthcare providers.

Disclosures
Sholzberg: Octapharma: Research Funding; CSL Behring: Research Funding; Amgen: Research Funding; Shire: Research Funding.
Kinetics of Iron Depletion in Hereditary Hemochromatosis
Authors: Sanz Cristina , Garcia-Carulla Anna , Pereira Arturo 
Published: October 2019

Abstract
Introduction: Hereditary hemochromatosis (HH) is a genetic disorder that results in an increased accumulation of dietary iron. The only effective treatment is iron depletion by phlebotomy or erytrocytapheresis (EA). The kinetics of iron depletion in response to these treatments has been little studied and its temporal profile and the influence of patient's factors are not fully known.
Objective: To describe the kinetics of iron depletion in patients with HH on phlebotomy or EA.
Material and methods: Patients in depletive treatment with phlebotomy (once per week) or EA (one every two weeks) were selected for this study if they had no associated inflammatory disorder, at least 3 ferritin determinations were available during treatment, and more than 70% of the established therapeutic schedule was fulfilled. The average reduction of serum ferritin was measured in ng/ml per ml of red blood cells (RBC) removed per Kg of patient's body weight, and was analyzed as natural logarithms (ln). Categorical variables were expressed as proportions and continuous variables, as median and interquartile range (IQR).
Results: Median age of the 34 included patients was 51 (44-58) years and 32 (94%) were men. Initial and final ferritin values were 1035 (IQR: 777-1564) ng/ml and 83 (IQR: 50-123) ng/ml, respectively. Transaminase levels were high (ALT> 50 U/L) in 9 patients, and 2 of them had been diagnosed with liver cirrhosis secondary to HH. With regard to genotype, 27 patients were C282Y homozygous, 4 were compound heterozygous (C282Y/H63D), 1 had a TFR2 mutation, and no mutation was found in 2. The average reduction of serum ferritin was 1.04 (IQR: 1.03-1.05) ng/mL per mL of removed RBCs/Kg of patient's body weight. Figure 1 shows the mathematical expression that best described the kinetics of serum ferritin.
The rate of serum ferritin reduction, as measured by this mathematical expression, was independent of the initial ferritin level, the total reduction of ferritin, the presence of high transaminase levels or cirrhosis, as well as the patient's age and body mass index. In contrast, the rate of ferritin reduction varied with the genotype; it was significantly lower in patients homozygous for the C282Y mutation than in patients with other genotypes (median: 1.03, IQR: 1.02-1.05 vs. 1.07, IQR: 1.06-1.11 ng/mL per mL of removed RBCs/Kg; p < 0.001; figure 2).
Conclusions: In patients with HH and good adhesion to the therapeutic schedule, the reduction of serum ferritin is predictable as a function of the volume of removed RBCs and the patient's weight. Patients homozygous for the C282Y mutation have a slower kinetics of iron depletion.

Disclosures
No relevant conflicts of interest to declare.