bluuebunny/crossref_metadata_2025_split huggingface dataset:
PS1173 PROTEIN CASEIN KINASE 2 IS INVOLVED IN CHRONIC MYELOID LEUKEMIA RESISTANCE TO IMATINIB AND ALSO TO DASATINIB
Authors: Mitrovský O. , Myslivcová D. , Macháčková T. Lopotová , Klamová H. , Žáčková M. 
Published: June 2019

Background:Protein casein kinase 2 (CK2) is a Ser/Thr kinase, which is ubiquitously expressed in eukaryotic cells. It phosphorylates a broad number of proteins, regulates a number of key signaling pathways and promotes cell proliferation and survival. Although CK2 does not belong to the “oncogenic kinases”, it is overexpressed in many solid tumours and also in hematological malignancies. Previous results by Donella‐Deana et al. indicated CK2 association with resistance to imatinib in CML cell lines. In our study, we explored the role of CK2 in cell resistance to imatinib as well as to dasatinib, both in CML cell lines and in patient samples.Aims:We aimed 1) to verify the involvement of CK2 kinase in the resistance to imatinib, in cell line model and in patient samples and 2) to investigate possible role of CK2 in the resistance to dasatinib.Methods:Sublines resistant to either 2 nM dasatinib or 2 μM imatinib were derived from established CML cell lines JURL‐MK1, MOLM‐7, and K562. Sensitive and resistant cells were then treated with the CK2 inhibitor CX‐4945, imatinib, or dasatinib, individually or in selected combinations. Alternatively, siRNAs against CK2 subunits were used. Cell viability was determined using Alamar test. Protein levels and phosphorylation were measured using western blots. CK2 activity was assessed through phosphorylation of its substrates [(pS/pT)DXE] and of its natural target, Cdc37. To evaluate the extent of apoptosis, PARP and caspase 3 cleavage was analysed.Results:We have successfully established JURL‐MK1, MOLM‐7 and K562 sublines resistant to either 2 nM dasatinib or 2 μM imatinib. We found increased protein levels of CK2 kinase and increased phosphorylation levels of CK2 substrates in all resistant cells as compared to sensitive cells. All cells were treated with imatinib, dasatinib and CK2 inhibitor CX‐4945 and their combinations. Despite the loss of response to TKIs, the resistant cells remained sensitive to CK2 inhibition. CX‐4945 reduced CK2 substrates phosphorylation and also cell proliferation in both type of resistant cells. It also increased apoptotic indicators (cleaved PARP, caspase 3) and the dead cell fraction. Preliminary results showed a decrease of cell viability and/or apoptosis induction also in primary cells from four patients resistant to imatinib or dasatinib. Leukocytes from healthy donors were not affected by any of the inhibitors tested.Summary/Conclusion:Altogether, our results suggest that CK2 kinase is involved in CML resistance to both imatinib and dasatinib. Further research is necessary to fully understand the role of CK2 in CML and its potential to become a new target of therapy.
PS1206 TRANSCRIPTION FACTOR BOB1 IS ESSENTIAL FOR GERMINAL CENTER‐DERIVED B CELL MALIGNANCIES OFFERING AN ATTRACTIVE TARGET FOR TCR‐BASED THERAPY
Authors: Reijmers R. , Meeuwsen M. , Kweekel C. , Kop M. , Meringa A. , Jahn L. , Falkenburg F. , Heemskerk M. 
Published: June 2019

Background:Antigen‐loss tumor escape variants are a major concern when targeting cancer, while tumor‐specific targeting is crucial to prevent unwanted toxicity. Thus, targeting essential cancer‐ or lineage‐specific genes might represent attractive targets for antineoplastic therapies since antigen‐loss is less likely to occur, and toxicity is limited. Here, we describe B cell lineage‐specific transcriptional coactivator BOB1 to meet these important criteria. Interestingly, in our lab we have successfully identified several distinct T cell receptors (TCRs) that are BOB1‐specific with demonstrable preclinical efficacy.Aims:With this study we aimed to demonstrate that the transcriptional coactivator BOB1 is essential for survival of B cell malignancies with a germinal center origin, and that these neoplasms are recognized by our recently and newly identified BOB1‐specific TCRs in the context of HLA‐B∗07:02 and HLA‐B∗35:01, respectively.Methods:Using a CRISPR/Cas9 puromycin plasmid containing a sgRNA or by applying a doxycycline‐inducible system, we set out to target BOB1 in different B cell malignancies. Upon targeting, we selected puromycin resistant single‐cell clones or tracked cell growth upon induction, and used sanger‐sequencing to identify possible indel mutations. Besides single‐cell analysis, Tracking of Indels by DEcomposition (TIDE) was used to accurately quantify the editing efficacy and most prominent types of indel mutation in different pools of B cell tumors. Finally, we performed in vitro co‐cultures with BOB1‐specific TCR transduced CD8 T cells and a plethora of B cell malignancies, including myeloma and lymphoma, and assessed preclinical efficacy targeting myeloma in vivo.Results:Remarkably, for each type of B cell tumor used, we were unable to generate BOB1‐deficient clones, unveiling the importance for cell survival. In line, using the TIDE algorithm for easy detection of predominant types of indel mutations in targeted pools of distinct types of B cell malignancies, we found unmutated BOB1 sequences only (>90%), while generally a mere 5% is expected to be unaltered for any irrelevant gene. Finally, we further established the essentiality of BOB1 in a broad panel of B cell malignancies containing inducible CRISPR/Cas9, which uniformly resulted in rapid cell death upon induction. Interestingly and importantly, using our recently and newly identified TCRs recognizing peptides derived from BOB1 in the context of HLA‐B∗07:02 and HLA‐B∗35:01, we observed highly specific and efficient targeting of a vast majority of B cell malignancies in vitro and in vivo.Summary/Conclusion:Altogether, we postulate BOB1 as an essential B cell lineage‐specific target, fortifying gene transfer of our unique TCRs into CD8+ cytotoxic T cells as an efficient therapeutic treatment option for a large variety of B cell neoplasms.
PS1284 GLOBAL GUIDELINE FOR THE DIAGNOSIS AND MANAGEMENT OF MUCORMYCOSIS: AN INITIATIVE OF THE ECMM IN COOPERATION WITH THE MSG ERC
Authors: Cornely O. , Chakrabarti A. 
Published: June 2019

Please indicate where the abstract has been published before: The Lancet Infectious DiseasesBackground:Mucormycosis is a rare disease that may progress rapidly. Although urgent surgical and medical intervention is lifesaving, diagnosis is often delayed and mortality rates are high. Guidance on the complex multidisciplinary management has the potential to improve prognosis. Management pathways depend on recognising disease patterns and availability of diagnostic and therapeutic options.Aims:To address differences between the regions of the world, authors from 33 countries analysed published evidence on mucormycosis management and provide recommendations as part of the “One World One Guideline” initiative.Methods:Consensus process involving experts from all UN regions, comprising physicians and scientists involved in various aspects of mucormycosis management, representing the fields of microbiology, pathology, radiology, infectious diseases, surgery, paediatrics, haematology, intensive care, dermatology, and pharmacology.Results:This guidance document provides practical help in clinical decision making and identifies areas of uncertainty and future research direction.Summary/Conclusion:Mucormycosis requires different tailored approaches in different regions of the world‐ This guidance document is the first in a series from One World One Guideline initiative.
PS1288 SAFETY AND UTILIZATION OF MIDLINE CATHETERS VERSUS TUNNELED CENTRAL VENOUS CATHETERS IN THE MANAGEMENT OF ACUTE MYELOID LEUKEMIA PATIENTS: A SINGLE CENTER EXPERIENCE
Authors: Gardeney H. , Gallego P. , Diaz J.M. Torregrosa , Cayssials E. , Maillard N. , Rammaert B. 
Published: June 2019

Background:Tunneled central venous catheters (TCVCs) are used in cancer patients for irritant or vesicant infusions such as chemotherapy or antibiotics. However, they can be associated with significant complications. Midline catheters (MCs) are peripheral intravenous access devices that ends in a large peripheral vein. They are easier to install and which may reduce the need for CVCs.Aims:Therefore, the aim of this study is to assess the rate of adverse events with both kind of catheter, in hospitalized patients for the treatment of acute myeloid leukemia.Methods:We retrospectively compared the use and complications of TCVCs and MCs at our institution between December 2017 and July 2018. Data were collected using electronic medical records. Both devices were used indistinctly among our hospitalized patients for chemotherapy, antibiotics and parenteral nutrition. The following complications were recorded: catheter‐related bloodstream infection (defined as documented bacteriemia and differential time to positivity pointing to TCVC as main source), local signs of infection (such as erythema or inflammation) at insertion site, thrombosis which requires an anticoagulant treatment, extravasation and local bleeding at insertion site.Results:Through this period, 59 chemotherapy episodes were recorded among 36 different patients: 39 of them were performed through TCVC and 20 through MC. As expected duration of the device was shorter for MCs (mean 31days) as they were ablated on discharge, compared to Hickman (51 days) or Port‐à‐cath (48days). Main complications were related to infections, with 17 (43.6%) among TCVCs and 6 (30%) in MCs (p = 0.4). Local signs of infection were also present on 5 (12.8%) of TCVCs. Median aplasia duration (defined as polymorphonuclear neutrophils count in peripheral blood <500/mm3) was 19.0 days [0 to 55 days], with no differences among the groups (18.3 days in MCs vs 19.7 days in TCVCs). No extravasation was found in any group. As expected local bleeding was not observed among MC and only in 3 (7.7%) TCVCs. There is a trend towards more frequent complications (infection, thrombosis and bleeding) were more frequent among TCVCs (n = 32) than among MCs (n = 6; p = 0.08) even when reported to the length of the catheter (0.63 complications/day in TCVCs and 0.19 complications/day in MCs).Summary/Conclusion:MCs insertion ‐quick and easy‐ makes them user‐friendly for hematologists and can be safely used among acute leukemia patients.
PS1293 OSTEOGENESIS IMPERFECTA: A NEW UNRECOGNIZED ETIOLOGY FOR FUNCTIONAL IRON DEFICIENCY
Authors: Elsayed S. , Ragab I. , Yacoup A. , Sallam M. 
Published: June 2019

Background:Osteogenesis imperfecta (OI) is a genetic disorder of connective tissue primarily affecting bone with a wide spectrum of clinical expression that varies from death in the perinatal period to normal life expectancy. Although data is scarce, we observed a high frequency of anemia in patients with OI and hypothesized that functional iron deficiency (FID) may occur secondary to the inflammation resulting from frequent fractures and multiple surgical procedures.Aims:The aim of this work was to study the frequency of anemia in children with OI and try to classify them according to iron status by conventional tests to analyze the possibility of presence of FID and the possible association of hepcidin level with such etiology.Methods:A cross‐sectional study included 56 patients diagnosed with osteogenesis imperfecta regularly following at the genetics clinic, Children'sHospital, Ain‐Shams university. All patients were subjected to detailed clinical scoring with complete blood count, serum iron, serum ferritin, and total iron binding capacity, C‐reactive protein (CRP) and serum hepcidin by ELISA, Dexa scan and lateral and AP spine x‐ray. Patients were classified into five groups, Group‐1 including 7 OI patients fulfilling criteria of FID; serum ferritin > 100ng/ml, TS < 20% and CRP> 1 mg/dl, Group‐2 including 27 OI patients fulfilling criteria of combined ACD&IDA; serum ferritin level was ≤ 100ng /ml, TS < 20% and CRP> 1 mg/dl, Group‐3 including 16 OI patients without anemia according to WHO classification, other anemia group including 6 OI patients with anemia that could not be classified according to the classification adopted in this study, IDA anemia including zero OI patients as there were no patients fulfilling criteria of pure IDA; ferritin < 12ng/ml in children aged <5 years, or ferritin <15ng/ml in children aged > 5 years, when the corresponding CRP was <1 mg/dl and TS < 20%.Results:The frequency of anemia among the studied patients with osteogenesis imperfecta was 71.4%. Combined IDA and FID formed 48.2%, 12.5%, 28.6% and 10.7% hadFID, no anemia and other anemia groups respectively. functional iron deficiency was found in 60.7%.Median hepcidin level was significantly increased in pure FID patients 120 (100 – 510 ng/mL) as compared to those in no anemia patients 80 (65 – 100 ng/mL) and other anemias 60 (50 – 70 ng/mL). The serum hepcidin concentration was mildly reduced in ACD patients with ID with a median of 100 (60 – 150 ng/mL).Patients with severity score levels less than 70% had significant higher number of WBCS, platelets and serum hepcidin levels and significant lower serum iron compared to patients with severity score levels more than 70% and less than 90%.Summary/Conclusion:Anemia is an unrecognized complication in patients with OI. Functional iron deficiency constitutes a significant etiology adding to dietetic problems. New therapeutic approach for FID is suggested to improve the quality of fracture healing in such group.
PS1297 EFFICACY AND SAFETY OF INTRAVENOUS IRON THERAPY IN CHILDREN: A KOREAN SINGLE CENTER STUDY
Authors: Jung N. , Shim Y.J. , Kim H.S. 
Published: June 2019

Background:Although Intravenous (IV) iron is widely and safely administrated to adults for various indications including severe anemia, chronic blood loss and postoperative anemia, Administration of IV iron is rarely used in children due to lack of pediatric data.Aims:The aim of this study was to determine the indications for IV iron and to evaluate the efficacy and safety of IV iron infusions to children who were visited a single Korean center.Methods:This retrospective study collected data from ≤18 year‐old children who were received IV iron at the Keimyung University Dongsan Medical Center between July 2003 to December 2018. Exclusion criteria included: (1) receiving a packed red blood cell transfusion or erythropoietin, (2) surgery or massive bleeding before obtaining the laboratory results of post IV iron infusion. We compared laboratory results including hemoglobin (Hb) concentrate, mean corpuscular volume (MCV), serum ferritin level between pre and post‐IV iron infusion. Also, the medical records were reviewed for adverse effects. All statistical analyses were performed using IBM SPSS software (version 23.0; IBM Corp., Armonk, NY), and P‐values of <0.05 were considered statistically significant.Results:Total 31 children (male:female = 18:13; median age 4.5 years, range 0.3–17.9) received total 80 infusions of IV iron therapy. The most common etiology of anemia was gastrointestinal cause. Oral iron intolerance (32%) and refractoriness (26%) were common indications for IV iron infusion. Seventeen patients received a total 43 infusions of iron sucrose (median dose, 3.9 mg/kg, range 1.0 to 20.4), fifteen patients received a total 37 infusions of ferric carboxymaltose (median dose, 5 mg/kg, range 3.3 to 18.8). All Patients had follow up laboratory test at 1–120 days (median 15 days) after their infusions. Except 2 patients, all patients showed good hematologic response. The median pre‐infusion Hb, MCV and ferritin values were 9.0 g/dL (range 6.1–13.6), 75.9 fL (55.9–94.3) and 12.2 ng/mL (1.7–284.9), respectively. The median post‐infusion Hb, MCV and ferritin values were 10.7 g/dL (6.3–14.7), 79.6 fL (64.9–103.5) and 54.0 ng/mL (3.9–842.8), respectively. There were statistically significant improvements in these values (p‐value <0.001). No patients experienced severe adverse effects such as anaphylaxis.Summary/Conclusion:The most common indication for IV iron among Korean children was oral iron intolerance. The use of IV iron is effective and safe treatment in children.image
PS1446 THE ROLE OF THE THROMBOPOIETIN RECEPTOR (MPL) IN JAK2V617F‐POSITIVE MYELOPLROLIFERATIVE NEOPLASMS
Authors: Behrens K. , Viney E.M. , Willson T.A. , Babon J.J. , Nicola N.A. , Alexander W.S. 
Published: June 2019

Background:Constitutive activation of the Jak/Stat signalling pathway is a hallmark of Myeloproliferative Neoplasms (MPN), with 60–90% of patients carrying the activating JAK2 mutation, JAK2V617F. Several studies suggest expression of a type I cytokine receptor is essential for JAK2V617F‐mediated transformation, but the precise contribution of such receptors is unresolved.Aims:Here we investigate the functional role of Mpl in JAK2V617F‐driven MPN.Methods:Mpl mutants lacking various functional domains were screened for their capacity to support JAK2V617F‐mediated factor independence in BaF/3 cells. Using CRISPR/CAS9 genome editing Mpl‐mutant mice were generated to extend these findings to an in vivo model of JAK2V617F MPN.Results:In vitro studies confirmed that Mpl expression was required for JAK2V617F‐induced transformation, but identified a Mpl truncation mutant retaining the JAK2‐interaction domain, but lacking the C‐terminus (Mpl‐IC36), typically associated with Stat5 binding, to be sufficient to support JAK2V617F‐induced transformation. Interestingly, Stat5‐phosphorylation was maintained. In contrast, deletion of the entire cytoplasmic receptor domain abrogated Stat5 phosphorylation and factor‐independent proliferation. In vivo Mpl‐wt;JAK2V617F mice exhibited the thrombocytosis and erythrocytosis typical of MPN, while Mpl deficiency abrogated thrombocytosis but sustained high red blood cell counts. Although the Mpl‐IC36 receptor was sufficient for JAK2V617F‐induced factor independence in BaF/3 cells, Mpl‐IC36;JAK2V617F mice did not develop thrombocytosis, indeed platelet counts were similar to those in Mpl null mice. This underlines differences that may emerge from in vitro and in vivo systems and highlights the important role of the Mpl cytoplasmic region for JAK2V617F‐mediated signalling.Summary/Conclusion:JAK2V617F requires Mpl to induce transformation. While a Mpl truncation mutant retaining the JAK2‐interaction domain, but lacking the C‐terminus (Mpl‐IC36) was sufficient to induce JAK2V617F‐mediated cytokine independence in BaF/3 cells in vitro, this receptor was insufficient for development of thrombocytosis in JAK2V617F mouse model. These results suggest that the role of Mpl in JAK2V617F‐induced MPN extends beyond a simple scaffold for active JAK2 and that signalling from the Mpl C‐terminal domain is required in vivo.
PS1474 NON‐HODGKIN LYMPHOMA IN PATIENTS WITH MYELOPROLIFERATIVE NEOPLASMS
Authors: Yoshinaga K. , Shiseki M. , Ryuzaki M. , Iizuka Y. , Watanabe A. , Tanaka N. , Ishiyama M. , Shinohara A. , Kazama H. , Hagiwara S. , Mori N. , Tanaka J. 
Published: June 2019

Background:Development of aggressive B‐cell lymphomas during JAK1/2 inhibitor therapy in patients with myeloproliferative neoplasms (MPN) were reported in 2018 European Haematology Association Meeting in Stockholm. It's important to evaluate the incidence of lymphomas in patients with ruxolitinib.Aims:We conducted a retrospective study to evaluate the incidence and clinical characteristics of lymphomas in patients with MPN.Methods:We reviewed laboratory data and clinical record of the patients with MPN diagnosed until Dec 2017 in Tokyo Women's Medical University Hospital.Results:Among 207 patients with MPN, including 129 essential thrombocytosis (ET), 68 polycythemia vera (PV), and 10 primary myelofibrosis (PMF), three patients (1.4%) developed an aggressive non‐Hodgkin Lymphoma (NHL) (Table). Among 207 patients with MPN 15 patients (7.2%) received ruxolitinib. Two of three patients developing NHL had a history of ruxolitinib treatment. There was significant difference in the incidence of NHL occurrence between MPN patients with ruxolitinib treatment (2/15, 13.3%) and those without ruxolitinib treatment (1/192, 0.5%) (Fisher's exact test, P = 0.014). Initial symptoms of lymphoma were extra‐nodal mass (cutaneous or colon mass) in two patients with ruxolitinib treatment. Times from starting ruxolitinib treatment to the diagnosis of lymphoma in these two patients were 2 and 16 months, respectively. They did not achieve complete response by anti‐lymphoma chemotherapy, and died from AML. In contrast, the DLBCL patient without ruxolitinib achieved complete response and is still alive.Summary/Conclusion:The occurrence of lymphoma was more common in patients with ruxolitinib than in the non‐administered group. Porpaczy et al reported that pre‐existing B‐cell clones in myelofibrosis developed to B‐cell lymphoma after ruxolitinib treatment. In the present cases, lymphoma occurred within relatively short period after starting ruxolitinib treatment, suggesting that there were pre‐existing lymphoma clones before ruxolitinib treatment. Extra‐nodal site involvements were seen in present cases similar to the previous reports, suggesting biological difference of lymphoma complicated with MPN patients. Unlike previous report, one T‐cell lymphoma case was included in the present study. It remains unclear whether there is difference in clinical features and mechanisms between B‐cell lymphoma and T‐cell lymphoma development in MPN patients with ruxolintinib treatment. It may be underestimated to the occurrence of lymphoma if biopsy may not perform depending on the condition of patient. We need to careful watch and actively examine the tumor in MPN.image