bluuebunny/crossref_metadata_2025 huggingface dataset:
PB1912 EFFICACY AND SAFETY OF RITUXIMAB BIOSIMILAR TRUXIMA IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA AND NON‐HODGKIN'S LYMPHOMAS
Authors: Micheva I. , Useir S. , Gercheva L.
Published: June 2019

Background:

Rituximab, an anti‐CD20 monoclonal antibody, is a key therapeutic in the treatment of B cell lymphomas and Chronic lymphocytic leukemia (CLL). TruximaTMis the first biosimilar of the medicine Rituximab to be approved for the treatment of patients non‐Hodgkin's lymphoma (NHL) and CLL, showing similar efficacy, pharmacokinetics, safety and immunogenicity profile. The use of biosimilars may reduce treatment costs andincrease patient access to Rtuximab.

Aims:

The aim of the study was to assess the efficacy and safety of TruximaTM treatment in combination with chemotherapy in patients NHL and CLL followed for 12 months.

Methods:

A total of fifty one patients, 28 men and 23 women, were treated with ruximaTMin the Clinic of Hematology at “Sveta Marina” University Hospital, Varna. TruximaTMwas applied at a dose of 375 mg/m2every 3 weeks in combination with chemotherapy. Response was estimated at treatment completion.

Results:

Median age was 68,5 years. 22 patients were with CLL, one Richter,s syndrome, 16 with Diffuse large B cell lymphoma (DLBCL), 4 with Mantel cell lymphoma (MCL), 4 with Ssmall cell lymphoma (SCL), 4 with Marginal cell lymphoma (MZL). TruximaTMwas combined with different chemotherapeutic regimens: CHOP in 11 patients, Bendamustin in 23, FC in 6, MINE in 3, ACVBP in 1, COP in 3, ICE in 1, and Leukeran in 1. In 34 patients TruximaTMwas applied as a first line treatment, in 12 patients as a second line, in 5 cases as a third line. 30 patients have completed their treatment at the time of analysis. Complete response was achieved in 9 (30%) patients, partial response in 17 (56,7%) patients, stable disease in 4 (13,3%). Progressive disease was observed in 1 patient with DLBCL. Grade 3 or 4 hematological toxicity was registered in 5 patients (9,8%). Infusion related reactions were observed in 5,8% of the patientsat grade 1 and 2.

Summary/Conclusion:

Our experience with the biosimilar over the last year has revealed that TruximaTM is an effective treatment without unexpected side effects. Moreover, cost may be a factor for doctor's choice.
PB1922 PONATINIB INDUCES A SUSTAINED DEEP MOLECULAR RESPONSE IN A CHRONIC MYELOID LEUKAEMIA PATIENT WITH AN EARLY RELAPSE WITH A T315I MUTATION FOLLOWING ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION
Authors: Cerveira N. , Ferreira R.B. , Bizarro S. , Correira C. , Torres L. , Lisboa S. , Vieira J. , Santos R. , Campilho F. , Pinho Vaz C. , Leite L. , Teixeira M. , Campos A.
Published: June 2019

Please indicate where the abstract has been published before: BMC Cancer.

Background:

Atypical BCR‐ABL1 transcripts are detected in less than 5% of patients diagnosed with chronic myeloid leukaemia (CML), of which e19a2 is the most frequently observed, with breakpoints in the micro breakpoint cluster region (μ‐BCR) and coding for the p230 BCR‐ABL1 protein. p230 CML is associated with various clinical presentations and courses with variable responses to first‐line imatinib.

Aims:

In the present study we describe in detail the clinical history of a CML patient with a rare e19a2 BCR‐ABL1 transcript who has failed several lines of targeted therapy with tyrosine kinase inhibitors and relapsed after allogeneic hematopoietic stem cell transplantation.

Methods:

Detailed characterization of the patient's clinical history including therapeutic approach and cytogenetic and molecular analysis.

Results:

Here we report a case a CML patient with imatinib resistance due to an E255 V mutation, followed by an early post‐transplant relapse with a T315I mutation that achieved a persistent negative deep molecular response (MR5.0) after treatment with single‐agent ponatinib. Using CastPCR, we could trace back the presence of the T315I mutation to all the RNA samples up to the detection of T315 mutation by Sanger sequencing shortly after allogeneic hematopoietic stem cell transplantation.

Summary/Conclusion:

This case illustrates the major interest of Ponatinib as a valid treatment option for e19a2 CML patients who present a T315I mutation following relapse after allogeneic hematopoietic stem cell transplantation.

image
PB1931 CARDIO‐ONCOLOGY UNIT IMPROVE THE MANAGEMENT OF TREATMENT WITH TKIS OF CHRONIC MYELOID LEUKEMIA PATIENTS: A SINGLE CENTER EXPERIENCE.
Authors: Spinosa G. , CAPALBO S.F. , CASAVECCHIA G. , ZICCHINO S. , DEL MASTRO M. , BRUNETTI N.D.
Published: June 2019

Background:

Although Tyrosine Kinase Inhibitors (TKIs) have revolutionated the treatment of Chronic Myeloid Leukemia (CML), it is importat to focus the attention about the safety of this class of drugs specially for cardiovascular adverse events (CVE), their “off‐ target” effects encompass a wide range of cardio toxicities, including left ventricular disfunction, electrocardiographic abnormalities with dysrhythmias, hypertension, myocardial ischemia and thromboembolic events. The long‐term safety call for a multidisciplinary effort embracing hematologists, cadiologists, nurses.

Aims:

demonstrate the usefulness of a cardio‐oncology unit in primary and secondary cardiovascular risk prevention in patients with chronic myeloid leukemia in treatment with TKIs

Methods:

From February 2005 to September 2018, 61 consecutive patients (27 women and 34 men) affected by CML were treated with TKIs at our institution. The patients underwent to clinical, laboratory and instrumental evaluations. Several informations about cardiovascular risk factors, lifestyle and concomitant medications, were collected with the support of a nurse, who administered to patients specific questionnaires. Patients were assessed at baseline and during follow‐up.

Results:

50% of patients already had cardiovascular disease at diagnosis, 35% of patients developed cardiovascular events during treatment.

16.6 % of patients presented risk factors unchangeable, while 83.4 % of patients presented risk factors related to incorrect lifestyle habits.

Before the intervention by cardio‐oncology unit, 65% of patients thought they knew the risks associated with the wrong lifestyle habits. After the intervention, the percentage of patients aware of the risk factors was 90% (p value <0.05: significance index). The therapeutic education program was considered very useful for this purpose by 95% of patients. 75% of patients said that their quality of life has improved during the observation period.

Summary/Conclusion:

CONCLUSIONS: In our institution, the Cardio‐oncology Unit deals with primary prevention and the secondary treatmet of cardiovascular disease therapy‐related. Our results confirm that a cardio‐oncology program applied to patients with CML can represent unique oppotunities and challenges to preserve cardiovascular health, to allow the timely delivery of cancer therapy and achieve disease free remission. Managment of treatment with TKIs of CML patients is multifaced and involve lifestyle education, pharmacotherapy, enhanced cardiovascular surveillance and support services.The optimal composition of cardio‐oncology team should involve support from cardiologist, oncologist and nurses.
PB1938 PERSPECTIVE OF THE PATIENT WITH CML AND FAILURE TO TREATMENT WITH IMATINIB AT AN ENVIROMENT OF LIMITED RESOURCES.
Authors: Osorno‐Rodríguez K.L. , Cantú‐Rodriguez O.G. , Gómez‐Villarreal J.P. , Ríos‐Rodelo M.R. , Lafarga‐Amao B. , Hawing‐Zárate J.Á. , Villalobos‐Gutiérrez L.E. , Gómez‐Almaguer D.
Published: June 2019

Background:

Chronic myeloid leukemia (CML) is a haematological malignancy caused by translocation t(9;22). The advent of imatinib meant a substantial improvement in the survival of patients compared to older therapeutic options such as busulfan, hidroxyurea and alfa interferon. The presence of resistance or failure to treatment to imatinib requires second‐line drugs such as dasatinib or nilotinib, however its correct access to the population with limited resources is restricted mainly by their costs.

Aims:

Evaluate the behavior and outcome of patients with a loss of response to imatinib who do not have access opportunately to a second of third line tyrosine kinase inhibitor (TKI).

Methods:

It's a retrospective, observational, longitudinal study of two medical centers. We collected all the demographic data and the laboratory values of the patients older than 18 years with a diagnosis of CML with failure to imatinib as well as its clinical evolution and the therapeutic measures taken.

Results:

We obtained the data from 139 patients attended between 2007 and 2018. The median age was 48 years (38‐59) in which 51.8% were males. 64.7% (90) has access to second‐line TKI in a timely manner with a median time between the loss of response and the start of the second‐line therapy of 3 months.

In the group without timely manner access, in 57.1% of the patients, the imatinib dose was increased, 14.3% continued imatinib at the same dose due to preservation of hematological response, 22.4% had Ara‐C and/or alfa interferon added to them therapeutic scheme and 18.3% entered to a clinical trial after which 81.2% continued in molecular failure. Of these patients, 44.9% had late access to a second‐line TKI with a median time of 29 months (15‐53), 10.8% developed blastic crises, and 10.2% underwent an allogeneic bone marrowa transplantion, of this subgroup currently 6.1% are in hematological failure and 26.5% are in molecular failure.

Of the group with timely access, 39% went to a third‐line TKI due to los of response to treatment, 6.7% developed blastic crises and 4.4% underwent allogeneic bone marrow transplantation, of this group currently 2.2% are in hematological failure and 10% are in molecular failure.

Summary/Conclusion:

In a population of limited resources such as ours, due to the lack of timely access to second‐line TKI as estabished by international guidelines, other options such as haematopoietic cell transplantation should be considered, in order to limit the risks that delaying the access to a second‐line TKI can cause.
PB1949 CHRONIC MYELOID LEUKEMIA PATIENTS WITH BOTH HIGH TH1 AND HIGH CD8+ T‐CELL LEVELS SHOW THE BETTER REMISSION, AND THE GOOD THERAPEUTIC RESPONSE ACCOMPANIES WITH THE HIGHER TH1 LEVEL
Authors: Dai J. , Yang X. , Wei Q. , Zou M. , Wang Y. , Li H. , Huang X. , Wang X.
Published: June 2019

Background:

The immune mornitoring on chronic myeloid leulemia (CML) patients may provide valuable guidence for the therapeutic strategies and prognosis prediction of this hematological malignancy.

Aims:

To investigate the correlation of Th1 and CD8+T‐based immunological characteristics of CML patients with the clinical efficacy.

Methods:

To analyze the Th1 proportion (Th1/CD4+T) and the CD8+T proportion (CD8+T/Lymphocyte) in the peripheral blood of all the CML patients diagnosed in our center. And the remission status at the same timepoint of the blood test are evaluated. The data is further statistically analyzed in different groups.

Results:

70% of the patients in newly‐diagnosed group (n = 10), 15.38% of the patients in complete cytogenetic response(CCyR) group (n = 13) and 15.15% of the patients in molecular response 4.5(MR4.5) group (n = 67) respectively show a Th1 level below the lower limit of normal, therefore, the low‐Th1 percentage of the newly‐diagnosed group is significantly higher than that of the CCyR group and that of the MR4.5group (P = 0.01; P = 0.00). On the other hand, the average of the actual Th1 value in the newly‐diagnosed group is also significantly lower than that in the CCyR group and that in the MR4.5 group (P = 0.01; P = 0.00). As we have observed in clinic work that those patients with both high‐Th1 and high‐CD8+T levels (both higher than the upper limit of normal) mostly obtain better remission situations, furthermore, we analyze the relevant groups of CML patients statistically in this study. The results show: The MR4.5 rate in the high‐Th1 and high‐CD8+T group (n = 15) is significantly higher than that in the high‐Th1 and not‐high‐CD8+T group (n = 17) (P = 0.03), while the un‐remission rate in these two groups doesn’t show a statistically significant difference (P = 0.74). On the other hand, the MR4.5 rate in the high‐Th1 and high‐CD8+T group is also significantly higher than that in the low‐Th1 and high‐CD8+T group (here “low‐Th1” represents that the Th1 level is below the lower limit of normal; n = 10) (P = 0.00), while the un‐remission rate in the high‐Th1 and high‐CD8+T group is significantly lower than that in the low‐Th1 and high‐CD8+T group (P = 0.00).

Summary/Conclusion:

The good therapeutic efficacy of CML patients after treatment shows a significantly higher Th1 level compared with the level at diagnosis. And those patients with a Th1 level and a CD8+T level both higher than the upper limit of normal show the higher remission rate and the deeper remission level.
PB1953 QUALITY OF LIFE AND SYMPTOM BURDEN WITH FIRST AND SECOND GENERATION TYROSINE KINASE INHIBITORS IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA
Authors: Toptas T. , Bostan H. , Kut K. , Pepedil Tanrikulu F. , Yilmaz F. , Atagunduz I. , Tuglular T.
Published: June 2019

Background:

With the advent of tyrosine kinase inhibitors (TKIs), patients with chronic myeloid leukemia (CML) have a life expectancy similar to those of age‐ and sex‐matched healthy population. Nevertheless, patients receiving TKIs report chronic adverse events, some of which may be associated with severe symptoms including fatigue, edema, muscle cramps. Additionally, generic imatinib has license in various countries. In retrospective analyses and post‐marketing safety monitorization, it seems to have a similar efficacy and safety profile. However, quality of life and symptom burden issues in patients receiving TKIs still remains to be elucidated

Aims:

We aimed to assess the quality of life and symptom burden in patients receiving original imatinib, generic imatinib, dasatinib, and nilotinib.

Methods:

A total of 121 patients with CML who have been receiving any TKI for at least three months was contacted either by phone or at their routine outpatient clinic visits. All patients accepted to be included in the study. Their demographic data were recruited from chart files. Quality of life was assessed by EORTC‐QLQ‐C30 and its CML24 module. Symptom burden was assessed by MD Anderson Symptom Inventory (MDASI). Questionnaire scores were calculated per associated protocols. Group comparisons were made by Kruskal Wallis test.

Results:

Median age of patient population was 53 (28‐90) years. Fifty‐four (44.6%) was female. Eighty‐three patients (81.4%) had Sokal low‐intermediate disease. Most of the patients had good ECOG performance status (<2: 96%) and low hematopoietic cell transplantation‐comorbidity index score (<3: 90.8%). Median duration of TKIs was 31 (3‐154) months. Ninety‐eight patients (86.7%) had major molecular response at the time of questionnaire. Patients receiving different TKIs had comparable quality of life and treatment‐related symptom burden scores (table and figure).

Summary/Conclusion:

First and second generation TKIs as well as generic imatinib have similar impact on quality of life. Although these molecules have different safety profiles, severity of treatment‐related adverse events are generally mild.

image
PB1959 THE ROLE OF FLOW CYTOMETRY IN DIFFERENTIAL DIAGNOSIS OF CMML AND REACTIVE MONOCYTOSIS. THE LIPID SIGNAL PATHWAY CHARACTERISTICS IN CLONAL MONOCYTOSIS
Authors: Sevoyan A. , Sevoyan A.
Published: June 2019

Background:

Myelodysplastic syndrome (MDS) is a heterogeneous group of diseases characterized by ineffective erythropoiesis and dysplasia. MDS and its subtype CMML is highly associated with chronic inflammatory and autoimmune diseases; however the combination of MDS with other bone marrow neoplasms is not a common entity. Only few cases of MDS combined with other blood malignancies have been described. The pathogenesis and mechanisms of two different clones evolution in MDS is an unclear multistep process involving molecular genetic instability, epigenetic factors and innate immune response deregulation. The role of plasma lipid signaling pathway have been also defined in recent years.

Aims:

Is to investigate the role of immunophenotyping in differential diagnosis of CMML and reactive monocytosis and clarify the possible significance of phosphoinositides in diagnosis of CMML.

Methods:

Blood samples of patient with CMML combined with plasma cell disorder, patient with CMML and blood samples of 2 patients with monocytosis were examined in our laboratory. Peripheral blood CBC, bone marrow smear cytological examination, pathohistology, flow cytometry and PCR were performed for the diagnostic purposes. In parallel with classic diagnostic work‐up the chromatograph method was used to investigate the cytoplasmatic mono and di‐phosphoinositides in patients with CMML.

Results:

CBC reveal monocytosis >1000 less than 1 month duration, PCR analysis were negative for BCR ABL in all 4 cases. Case N = 1 histology examination Results: >30% of plasma cells express CD56 and CD138, atypical cells express MPO and CD14 and epithelioid granulomas. In case N = 1 Immuntophenotype results were the following: (CD64+)‐52%, (CD16+)‐44%, (CD14‐). In case N = 2 the dysplasia, megakaryocytes and monocytes were observed by histology examination. Immunophenotype Results: (CD14+/CD16)‐31.1%, (CD14+/‐CD16+)‐49.3%, (CD14‐/CD16‐)‐4.3%. There were monocytosis and secondary changes of hematopoietic tissue in histology examination of cases N = 3 and N = 4. Immunophenotype showed: (CD14‐/16‐)‐13%, (CD64+)15%, (CD56‐)‐3%. High level of mono and di‐phosphoinositides were registered in first 2 cases in compare with cases N3 and N4. The flow cytometry revealed monocyte specific markers in all 4 cases with certain variations.

Summary/Conclusion:

The exact immunophenotype markers for clonal monocytosis must be defined. Lipid signaling pathway components, such as cytoplasmatic mono and di‐phosphoinositides must be investigated in the context of clonal monocytosis and diagnostic purposes.
PB1968 TWO NEW MUTATIONS AND MOLECULAR CHARACTERIZATION OF G6PD GENE AMONG THAI CHILDREN WITH G6PD DEFICIENCY
Authors: Traivaree C. , Boonyawat B. , Photi‐a A. , Monsereenusorn C. , Phetthong T.
Published: June 2019

Background:

Glucose‐6‐phosphate dehydrogenase (G6PD) deficiency is the most common X‐linked inherited erythroenzymopathy in Thailand. The clinical and hematological manifestations of G6PD deficiency is variable.

Aims:

This study aimed to characterize the spectrum of G6PD gene mutations in Thai pediatric patients who were followed‐up in Phramongkutklao Hospital, a tertiary center in central Thailand.

Methods:

A total of 102 children including 73 males (71.6%) and 29 females (28.4%) were included in our study. Mutation analysis was performed by direct DNA sequencing of the G6PD gene. Neonatal hyperbilirubinemia was the most common (87.3%) clinical manifestation in this study.

Results:

Molecular analysis of G6PD gene in 102 G6PD‐deficient Thai children identified a total of 12 mutational types. G6PD Viangchan (871G>A) was the most common (46.2%) identified mutation. G6PD Canton (1376G > T) was the second most common and was identified in 15.4%, followed by G6PD Kaiping (1388G > A) 14.4% and G6PD Mahidol (487G > A) 8.6%, respectively. Eight uncommon G6PD mutations including G6PD Quing Yan (392G > T) (3.8%), G6PD Aures (143C > T) (1.9%), G6PD Coimbra (592C > T) (1.9%), G6PD Songklanagarind (196T > A) (1.9%), G6PD Union (1360C > T) (1.9%), G6PD Valladolid (406C > T) (1.9%), G6PD Chinese‐5 (1024C > T) (1%) and G6PD Mediterranean (563C > T) (1%) were identified in this study. G6PD Valladolid and G6PD Aures were firstly identified in Thai populations.

Summary/Conclusion:

This study characterizes the molecular heterogeneity of G6PD variants causing G6PD deficiency in Thai children. Our study demonstrated the efficiency of direct DNA sequencing which can identify mutations in all 102 patients.
PB1970 AUOTOIMMUNE HEMOLITIC ANEMIA (AIHA) IN CHILDHOOD. IS PRIMARY IMMUNE DISORDERS MORE OFTEN THAN EXPECTED IN ETIOLOGY OF SECONDARY AIHA
Authors: Patiroglu T. , Alper O. , Cansever M. , Unal E. , Yilmaz E. , Karakukcu M.
Published: June 2019

Background:

Auotoimmune hemolitic anemia (AIHA) results from redcell destruction due to circulating antibodies against redcell membrane antigens. They are classified etiologically into primary and secondary such as primary immune disorders (PID), infectious disease and connective tissue disorders (CTD).

Aims:

Herein, we aimed to evaluation of etiology in cases with AIHA.

Methods:

62 cases diagnosed on positive direct antiglobulin test (DAT)at department of pediatric hematology in Erciyes University Hospital were included in the study and their records have been retrosectively examined.

Results:

Mean age of all cases was 61.9 ± 51.9 months (range of 1‐92 months). The cases showed a male predilection (M:F = 1.2). The results showed that 34 of 62 cases had primary 28 secondary AIHA (12 PID, 7 infections, 4 CTD, 3 Hodgkin disease, 2 endocrinopathies) respectively. Mean Hb value in cases with AIHA was 6.9 ± 2.5 g/dl and mean Hb value in cases with secondary AIHA was 6.8‐2.6 g/dl. All of them had mean low level of haptoglobulin (7.2 mg/dl in primary AIHA, 6.2 mg/dl in secondary AIHA) and they had mean high level of total bilurubin (4.9 mg/dl in primary AIHA and 1.4 mg/dl in secondary AIHA). There was no significant difference of mean Hb value in two groups (p = 0.783) but there was significant difference of mean bilurubin value in two groups (p = 0.001). One Case with secondary AIHA had IgM cold autoantibody and 61 cases had IgG warm autoantibody. The cases with primary AIHA had more strong positive IgG autoantibody than the cases with secondary AIHA and there was significant difference of IgG autoantibody positivity in two groups (p = 0.044).

Summary/Conclusion:

AIHA presented with severe anemia and laboratory evidence of marked hemolysis. Especially, PID is more often than expected in etiology of secondary AIHA.
PB1987 SELECTIVE ACTIVATION OF TOLEROGENIC CELL DEATH PATHWAYS IN MESENCHYMAL STROMAL CELLS
Authors: Savoldelli R. , cheung T. , Galleu A. , Dazzi F.
Published: June 2019

Background:

Mesenchymal stromal cells (MSCs) have been successfully employed for their tolerogenic and immunosuppressive capabilities in different conditions. We have demonstrated that, following infusion, MSCs undergo apoptosis and that this apoptosis results in an immunosuppressive activity. However, it is unclear how MSCs respond to different death inducing stimuli and whether MSCs from different sources respond similarly when following analogous patterns.

Aims:

To characterize the molecular response of MSCs, obtained from different sources, to distinct cell death stimuli.

Methods:

MSCs were isolated from human bone marrow (BM‐MSCs) or umbilical cord (UC‐MSCs) of healthy donors and exposed to recombinant human Tumor necrosis factor‐a(TNF‐a) and Interferon‐g(IFN‐g) in combination or individually, anti‐FAS (activator), TNF‐related apoptosis‐inducing ligand (TRAIL), phytohemagglutinin (PHA) activated Peripheral Blood Mononuclear Cells (PHA‐aPBMCs), hydrogen peroxide (H2O2) with or without the presence of the pan‐caspase inhibitor Z‐VAD. After 24 h, the cells were harvested and stained for annexin V/7‐AAD and analyzed by flow‐cytometry. The cancer cell line MCF‐7 was used as a positive control.

Results:

BM‐MSCs showed high sensitivity to apoptosis induction when treated with FAS activator (11% of AnnV+/7‐AAD‐ and 72% AnnV+/7‐AAD+) and PHA‐aPBMCs (7% of AnnV+/7‐AAD‐ and 78% AnnV+/7‐AAD). Conversely, UC‐MSCs were more resistant to apoptosis mediated by FAS, since the percentages of AnnV+/7‐AAD‐ and AnnV+/7‐AAD+ were 63% and 9%. Both BM‐MSCs or UC‐MSCs were only marginally sensitive to TRAIL (35% of apoptosis). In all cases, apoptosis induction was caspase dependent, as demonstrated by the significant reduction (p < 0.001) of the proportion of apoptotic cells in both BM‐MSCs and UC‐MSCs in the presence of the pan‐caspase inhibitor Z‐VAD. Conversely, neither BM‐MSCs or UC‐MSCs were induced to undergo apoptosis when treated with TNF‐aalso at very high concentrations or in combination with IFN‐g. The efficacy of the recombinant TNF‐ain inducing cell death was confirmed by using the cell line MCF‐7 as sensitive controls. Finally, all MSCs were sensitive to H2O2.

Summary/Conclusion:

MSCs exhibit varying susceptibility to different apoptotic stimuli. Interestingly, although this property seems to be maintained across different tissues of MSC origin, we could find variable degrees of sensitivity to specific stimuli, thus suggesting that different MSCs may play distinct roles according to the specific environment.
PB1988 CANCER‐ASSOCIATED MECHANISMS OF MESENCHYMAL STEM CELLS REVEALED BY SINGLE‐CELL TRANSCRIPTOME ANALYSIS
Authors: Stucky A. , Chen X. , Li C. , cai J. , Zhang X. , Zhong J.
Published: June 2019

Background:

The detrimental effects of mesenchymal stem cells (MSCs) in some reports eclipse their benefits in clinical application, despite the support and adoption in bone marrow transplantation (BMT). Tumorigenicity has been observed and reported in experimental MSC therapies without clear explanation.

Aims:

Here we report a subpopulation of MSCs, which are resisted to oste single‐cell transcriptome analysis of individual MSCs at various stages of osteocyte differentiation and gene expression profiles in three discrete stages of osteogenesis.

Methods:

We identified a subpopulation of osteogenesis‐resistant MSCs which have cancer stem cell chatcteristics. Further pathway analysis indicated that the YAP1, β‐Catenin and Cadherin4/6 pathway involved in osteogenesis‐resistance.. Clinical surveys using 51 clinical databases across 6,965 patients revealed a correlation between YAP1/ β‐Catenin/Cadherin4/6 overexpression and cancer progression.

Results:

This study suggested that a differentiation‐resistant population of MSC is repsoible for the tumorogenicity of MSC, and intervention of the YAP1, β‐Catenin and Cadherin4/6 pathway could potentially prevent tumorgenicity in MSC therapies. suggests that there is a pre‐exist subpopulation of MSCs with cancer stem cell characteristics.

Summary/Conclusion:

Those OR‐MSC associated with active YAP1‐Cadherin pathway. Biologically active molecules targeting YAP1/ β‐Catenin/Cadherin could improve MSC therapy for a defined subset of patients by minimize the tumorgenicity of MSCs.
PB1989 SHORT‐TERM APPLICATION OF CAFFEIC ACID SPECIFICALLY PROMOTES EXPANSION OF HEMATOPOIETIC STEM CELLS
Authors: Liu Y. , Wang R. , Liu Y. , Liu X. , Wang Y. , Hou M.
Published: June 2019

Background:

Caffeic acid (CFA) is a commonly used medicine in China for treatment of various causes of thrombocytopenia and leukocytopenia, but the mechanism is unclear.

Aims:

To investigate the effect of CFA on umbilical cord blood hematopoietic stem cells (UCB–HSCs) in vitro and explore the differentiated effect of CFA on cell expansion and differentiation in various tissues in vivo.

Methods:

CD34+ HSCs were isolated from cord blood and cultured for expansion. After 7 days’ culture with CFA, the total cell number and proportion of CD34+ cells were detected. Differentiation ability was analyzed by colony formation assay and megakaryocytes inducing assay before and after expansion. Additionally, CD‐1 mice were administered with CFA or vehicle for 14 days and BrdU injection started from day 7. Blood cell count was examined every 3 days. The proportion in bone marrow nucleated cells and BrdU insertion rate of HSCs were detected by flow cytometry. Besides, the percentage and BrdU insertion rate of Lgr5+ stem cells in intestinal mucosa, Sca‐1+ cells in lung and CK‐18+ epithelial cells in kidney were also analyzed.

Results:

In HSC expansion tests, the mean number (4.40∗10^5/well) and proportion (60%) of CD34+ cell in CFA groups were significantly higher than controls (4.00∗10^5/well; 48%). In HSC colony formation assay and megakaryocytes inducing assay, there were no significant difference between CFA groups and control. In vivo, the mean proportion (1.59%) and BrdU insertion rate (5.18%) of HSCs in CFA groups were higher than control (0.65% and 2.24%). No statistical differences were observed in other tissues.

Summary/Conclusion:

CFA can promote expansion of UCB–HSCs. Administration of CFA for 14 days specifically increased the proportion and DNA synthesis rate of bone marrow HSC in mice.

image
PB1994 HEMATOPOIETIC STEM CELL EXPANSION IN THE PRESENCE OF NICOTINE AMIDE AND IN THE MICROFLUIDIC DEVISE AND THE DBM SCAFFOLD
Authors: Asgari M. , asgari M.
Published: June 2019

Background:

The low number of umbilical cord blood cells is an important barrier to successful bone

marrow transplantation. Therefore, the growth of these cells while maintaining their

functional characteristics is of great importance

Aims:

Using microfluidic technology as well as

culturing cells on 3D scaffolds like DBM has greatly contributed to the simulation of the

mechanical and chemical micro‐environment of the bone marrow tissue. There are also

specific compounds for proliferation without differentiation of cells, one of them is

nicotinamide

Methods:

In this study, hematopoietic stem cells were cultured 7 days in two groups: 1.

In DBM in the microfluidic device 2. In DBM in the static state (control), under the following

Conditions:

1.negative control with feeder

2.cytokine+feeder

3.nicotinamide+feeder

4.nicotinamide+cytokine+feeder

After 7 days, cell count, real‐time PCR, their purity using flow cytometry, Colony forming unit assay

and apoptosis was evaluated. The status of the cells on the scaffold was observed using

electron microscopy.

Results:

Our results indicated that more cells were counted in static culture

than microfluidic culture (perfusion), while the ability of cell colonization in microfluidic

culture was far higher. The purity of HSCs was higher in microfluidic culture, and fewer cells

entered the apoptotic phase.

Summary/Conclusion:

Nicotinamide by preventing epigenetic changes resulting from laboratory cell culture, and

the microfluidic device associated with DBM by simulating bone marrow niche is a very

a suitable compound for the development of these cells.
PB2005 LONG TERM SURVIVORS HODGKIN'S LYMPHOMA: A SINGLE CENTER EXPERIENCE
Authors: Gaudio F. , Perrone T. , Curci P. , Russo Rossi A.V. , di Noi M. , Urbano M. , Piccolomo A. , Laddaga F.E. , Zucano S. , Arcuti E. , Specchia G.
Published: June 2019

Background:

Since the introduction of modern radiotherapy and combination chemotherapy, Hodgkin lymphoma (HL) has become a highly curable malignancy with 5‐year survival rates of more than 80%. However, the life expectancy and quality of life of HL survivors are reduced by the occurrence of late adverse treatment effects.

Aims:

This retrospective study was focused on 96 patients with newly diagnosed HL treated at the University Hospital of Bari (Italy) between 2005 and 2008.

Methods:

Median age at diagnosis was 35 years (range 15‐83), 33 pts (34%) presented advanced stage (III‐IV), 43 (45%) bulky disease, 45 (47%) presented B symptoms, 26 (27%) extranodal disease.

First line chemotherapy was ABVD in all the patients. The median number of chemotherapy lines was 1 (1‐5), 49 patients (51%) had undergone radiotherapy

Results:

At the end of treatment, 75 patients (78%) were in CR, and 24 patients (25%) in PR; 18 patients (24%) relapsed after a median follow‐up of 54 months (range: 12 – 62 months); 20 (21%) underwent autologous hematopoietic stem cells transplantation, 3 (3%) allogeneic stem cell transplantation.

After a median follow‐up of 12 years, 83 patients (86%) remain alive and 13 (14%) have died (4 of A second neoplasia, 1 of infection, 8 of the disease). The 10‐year Kaplan‐Meier survival estimates were 84%. Three women were pregnant and 3 healthy children were born. The most prevalent chronic conditions At last follow‐up were: overweight/obesity (65%), elevated fasting glucose (38%), high total cholesterol (34%), and hypertension (25%).

Summary/Conclusion:

Results of this study offer indications about how long after the initial treatment the excess deaths from causes other than Hodgkin's disease begin to occur. However, challenges remain in establishing the optimal time to begin screening for potential late complications and in developing better surveillance guidelines. Further work is also needed to identify risk factors that may predict specific late effects.
PB2007 PRELIMINARY RESULTS OF USING BRENTUXIMAB VEDOTIN IN RELAPSE/REFRACTORY HODGKIN'S LYMPHOMA.
Authors: Jazyltayeva A. , Gabbasova S. , Kemelbekov N. , Karakulov R. , Nassypov B. , Sagyndikov G. , Ishkinin E. , Akanov A. , Taktybayeva A. , Mirzayeva M. , Seidlazym M.
Published: June 2019

Background:

Hodgkin disease (HL) is curable disease in up to 80% of patients, but for the remaining relapse/refractory patients no standard salvage therapy exists. Brentuximab vedotin comprises an anti CD30 antibody conjugated by a protease‐cleavable linker to a microtubule‐disrupting agent.

Aims:

The aim of the study is to evaluate the outcome of patients with relapse/refractory form of HL, who received Brentuximab vedotin.

Methods:

In our Institute 21 patients with HL were treated, from 2015 till 2018 years. 17 (81%) patients had a primary‐resistant form, four (19%) patients had relapse of the disease.

The average age was 34.5 years (from 20 to 69 years), the average number of courses of therapy is 5.38 (from 3 to 8 courses). The mean follow‐up period was 17.9 months (from 4.1 to 38.1 months).

Results:

We have analyzed the survival of patients who received treatment. 21 patients who entered the study at the time of collection of information, 15 (71.4%) patients were alive. Median survival was 33.2 months. The standard error (SE) is 3.3 months, with 95% CI (26.8 ‐ 39.6).

Among patients with a primary resistant form, 13 (76.5%) patients were alive, with a median survival of 28.1 months, a SE of 2.3 months of 95% CI (23.6–32.6). Among patients with a non‐primary resistant form, two (50%) patients were alive, while the median survival was 9.1 months, SE 2.4 months 95% CI (4.5–13.7). Eleven patients had a partial response to treatment (52, 4%), ten of them (90.9%) were alive, while the median survival was 27.9 months, SE 2.3 months 95% CI (23.5 ‐ 32.4).

In three (14.3%) patients, a complete response to treatment was noted, of which three (100%) patients were alive. Cancer progression was noted in seven (33.3%) patients, two of them (28.6%) were alive, while the median survival was 27.9 months, SE 2.3 months 95% CI (23.5 ‐ 32.4).

In analyzing six (28.6%) patients had AutoSCT, and 15 (71.4%) patients did not, due to low stem cell growth. Among patients, which didn’t have AutoSCT 11 (73.3%) patients were alive, with a median survival of 30.4 months, a SE of 2.7 months of 95% CI (25.1 ‐ 35.7). When analyzing the causes of mortality, all patients indicated the cause of death from the progression of cancer.

Summary/Conclusion:

The analysis of the results using Brentuximab Vedotin showed good results in treatment of relapse and refractory forms of HL. In patients who failed to perform autologous stem cell transplantation, showed median survival of 30.4 months. This indicates the possibility of using the drug as an alternative to this procedure for the primary resistant form of the disease or further therapy options.
PB2023 SPORADIC CASES OF MALARIA IN NORTHERN GREECE, A MALARIA FREE COUNTRY
Authors: Tsioni K. , KARANTANI K. , PYRPASOPOULOU A. , TSAMIS E. , ISSA M. , VAGDATLI E.
Published: June 2019

Background:

Malaria is a disease caused by protozoa of the genus Plasmodium and the main hosts are arthropods. Human transmission is preceeded by female mosquito Anopheles bite. Human pathogens are Plasmodium vivax, falciparum and malariae, Less common are Plasmodium ovale and knowlesi. Since 1974, Greece is a Malaria free country. Nevertheless, sporadic cases are reported.

Aims:

We report five cases of malaria admitted in a tertiary care hospital of Thessaloniki.

Methods:

Five patients, 15‐34 years old were admitted consecutively, in three different departments of a tertiary care hospital in northern Greece from 2/10/2018 to 10/10/2018 due to fever, fatigue and night malodorous sweats. All five patients were relatives. Two sisters, living in the same house and their cousin with her two children, living in the same residential area. None of them had recently travelled in an epidemic county or had a blood transfusion. The diagnosis was based on a peripheral blood smear which was performed due to anemia, thrombocytopenia and neutropenia reported upon admission of the first patient. Characteristic ring forms, merozoites, trophozoites inside red blood cells and gametocytes were observed. Rapid malaria test revealed non‐falciparum infection and samples for molecular diagnostic testing were collected. Molecular analysis established Plasmodium vivax infection. All patients were treated with atovaquone 250 mg/ proguanile 100 mg per os, 4 pills once a day, for three days. Patients responded promptly and continued eradication therapy with primaquine for the next 14 days. Patients follow up included weekly visits at the hospital, blood testing with FBC, peripheral blood smears and rapid malaria testing, for three consecutive weeks in order to establish Plasmodium full elimination.

Results:

All patients were cured without complications. Due to the severity of the disease, the Greek Center of disease control was called to locate the source of the disease and take action concerning public health.

Summary/Conclusion:

Given the fact that malaria is not a common diagnosis, clinicians should have a close collaboration with the laboratory, even in malaria free countries. New sporadic cases can be found due to population migration. Increased rainfall, also affects malaria transmission because it increases relative humidity, modifies temperature and affects mosquito population and is a probable cause for those five cases in Thessaloniki. All cases must be reported as soon as possible and general population should be protected. Prompt diagnosis and treatment are in favor of the patient and general population.
PB2030 COMBINATION OF INVASIVE ASPERGILLOSIS AND INVASIVE CANDIDIASIS IN ONCOHEMATOLOGICAL PATIENTS
Authors: Shagdileeva E. , Shadrivova O. , Shneyder T. , Ermolova S. , Bogomolova T. , Ignatyeva S. , Klimko N.
Published: June 2019

Background:

Candida spp. and Aspergillus spp. are the most common fungal pathogen an oncohematological patients. Publications about combination of invasive aspergillosis (IA) and invasive candidiasis (IC) are limited.

Aims:

To investigate the frequency, risk factors, treatment outcome in patients with combination of IA and IC.

Methods:

Retrospective analysis of 800 adult patients with proven and probable IA in 1998 ‐ 2017 yy. For the IA and IC diagnosis criteria EORTS/MSG, 2008 were used.

Results:

IC was detected in 10 patients, 1.25% of all IA patients. The patients’ age was from 18 to 59 years (median ‐ 37), men ‐ 60%. Among the underlying conditions acute leukemia prevailed ‐ 60%, lymphoma ‐ 10%, aplastic anemia ‐ 10%, and hemolytic uremic syndrome – 10%.

Main risk factors were prolonged neutropenia – 90% (median – 10 days), lymphocytopenia ‐ 70% (median – 19 days), ICU stay – 50%, and glucocorticosteroid therapy – 40%.

The main clinical variant of IC was candidemia (100%) with liver (10%) or spleen (10%) involvement. The main sites of IA were lungs (100%) and sinuses (20%).

Diagnosis of IC was confirmed with blood culture in all patients: C. krusei – 40%, C. parapsilosis – 30%, Candida spp. – 30%. Positive galactomannan test in bronchoalveolar lavage (BAL) was in 80% patients. Microscopy of BAL revealed septated mycelium in 20% patients, BAL culture was positive (A.flavus) in 20% cases.

All patients received antifungal therapy (voriconazole ‐ 60%, amphotericin B deoxycholate ‐ 60%, fluconazole – 30%, lipid amphotericin B – 20%, posaconazole – 20%). In patients with IA and IC 30‐days overall survival rate was 60%, 12‐weeks overall survival rate – 40%.

Summary/Conclusion:

Invasive candidiasis was detected in 1,25 % of patients with invasive aspergillosis. Main risk factors were prolonged neutropenia and lymphocytopenia, ICU stay, and glucocorticosteroid therapy. The main agents of invasive candidiasis were C. krusei ‐ 40% and C. parapsilosis – 30%. The main clinical variant of invasive candidiasis was candidemia (100%) with liver (10%) or spleen (10%) involvement. In patients with invasive aspergillosis and invasive candidiasis 30‐days overall survival rate was 60%, 12‐weeks overall survival rate – 40%.
PB2034 INVASIVE ASPERGILLOSIS IN PEDIATRIC PATIENTS WITH MALIGNANCIES
Authors: Dinikina Y. , Shadrivova O. , Belogurova M. , Ignatyeva S. , Bogomolova T. , Boichenko E. , Klimko N.
Published: June 2019

Background:

Invasive aspergillosis (IA) is an important cause of infectious morbidity and mortality in immunocompromised pediatric patients. Early recognition and initiation of antifungal treatment are key to the infection control and possibility to continue anticancer treatment.

Aims:

To evaluate risk factors and treatment results of IA in children with malignancies.

Methods:

Retrospective analysis of the pediatric register of IA in malignancies from 1997 to January 2019. For the probable and proven IA diagnosis EORTC / MSG, 2008 criteria were used.

Results:

46 pediatric patients with malignancies were included, median age ‐ 8 years, males – 69,5%. IA was diagnosed after cytostatic chemotherapy in 42 patients (91,3%), in debut of cancer prior to chemotherapy – 4 (8,7%). Hematological malignancies were underlying diseases in 39 patients (84,7%), solid tumors – 7 (15,2%). Most frequent hematological diagnoses were myeloid leukemia (34,7%) and acute lymphoblastic leukemia (34,7%). Among solid malignancies – central nervous system tumors (42,8%). Risk factors of IA were prolonged ≥10 days neutropenia – 82,6%, steroid therapy – 50%, long‐term lymphocytopenia – 45,6%, severe bacterial infections (30,4%), and cytomegalovirus infection (8,8%). Main site of IA were lungs (89,1%), clinical signs were non‐specific. Typical imaging findings included the halo sign – 32,6% and air crescent sign – 4,3%. Galactomannan test in bronchoalveolar lavage fluid was positive in 83 %, in serum and cerebrospinal fluid – 37%. Mycological examination of specimen was attempted in 25% of patients. Among them septated hyphae by microscopy was diagnosed in 20%. Aspergillus spp. were isolated in culture in 28%. The etiology agents were A.fumigatus – 57%, A.niger – 29%, and A.ustus – 14%. Antifungal treatment received 100% of patients, with voriconazole only – 54,3%. 12‐week survival was 81%. In all cases of IA before chemotherapy after infection control anticancer therapy was continued. 63% of patients continued antifungal therapy concomitantly chemotherapy, voriconazole was canceled during vincristine use.

Summary/Conclusion:

Cases of IA in children with hematological malignancies were registered more frequently compared to solid tumors (84,7% vs 15,2%). The main risk factors of IA were prolonged neutropenia (82,6%), steroid therapy (50%), lymphocytopenia (45,6%). 12‐weeks overall survival was 81%. There were no contraindications for anticancer therapy to continue after infection control. In cases of continuation of antifungal treatment drug‐drug interactions should be considered.
PB2037 CHANGES IN ERYTHROPOIESIS IN MALARIA‐INDUCED ANEMIA
Authors: Pêgo A.C. , Lima I. , Martins G. , Sá Pereira I. , Martins A.C. , Kapitão A. , Nai A. , Camaschella C. , Silvestri L. , Gozzelino R.
Published: June 2019

Background:

Severe malarial anemia (SMA) is a complication developed in the course of Plasmodium infection, which is often associated with increased rates of malaria‐related morbidity and mortality. Possibly linked to a dysregulated immune response and unbalanced production of inflammatory mediators, one of the main features of SMA involves an impaired and/or ineffective erythropoiesis, which seems to critically contribute to the high number of deaths due to malaria infection. Erythropoiesis is regulated by the hormone erythropoietin, which upon binding to its receptor, activates a signaling cascade that leads to an increased consumption of iron used for the production of red blood cells.

Aims:

To gain new insights into the pathogenesis of malaria infection, our study aims to assess how erythropoiesis changes in mice exposed to different strains of Plasmodium parasites, known to cause severe forms of malaria, and/or in response to multiple re‐infections.

Methods:

Flow cytometry analyses were used to show the complementarity between the bone marrow and spleen in regulating the erythropoietic response in infected‐mice and its correlation with parasite load.

Results:

The interplay between this phenomenon and the expression of genes regulating iron metabolism was also analyzed, showing a strict association with the severity the disease. The extent of immune response activation upon exposure to Plasmodium infection was also evaluated and linked to the degree of induced SMA.

Summary/Conclusion:

The results obtained demonstrated that malaria infection significantly alters the erythropoietic process. In particular, we observed an early response of the spleen, as to compensate the loss of an appropriate bone marrow erythropoiesis during the infection.
PB2038 EVOLUATION OF CLINICAL MANIFESTATION IN FEBRILE NEUTROPENIC PATIENTS
Authors: Bekoz H.S. , Kaya Z. , Mert A.
Published: June 2019

Background:

Neutropenia is one of the most life‐threatening and significant complication of intensive chemotherapy treatments. Febrile neutropenia is the major cause of mortality and morbidity in these patients (1).

Aims:

The aim of this study, was to evaluate the epidemiology and the surveillance factors in febrile neutropenic patients retrospectively.

Methods:

This study was undertaken in the our university from December 2014 to December 2017. Blood culture was studied by Bact‐Alert automated system.Antibiotic susceptibility tests were Kirby Baver Discus Fusion Method.

Results:

A total of 195 patients, 400 febrile neutropenic attacks were assessed.

During FEN episodes, 178 of the patients (45%) had piperacillin‐tazobactam, 145(45%) had meropenem, 195(49%) had teicoplanin and 17(4%) had cefepime.In our study, microbiologically documented infection was 31%, clinically documanted infection was 33%, and responding to empirical antibiotic infection was 43%.

image

In our study, 83 blood culture positivity were studied for resistance, 33 (40%) of them had ESBL and 19 (23%) had carbapenemase‐producing microorganisms.

image

Summary/Conclusion:

For the management and determining empirical antibiotic policies, it is important to identify their pathogenic microorganisms, to determine their antimicrobial susceptibility for improving survival rates in FEN process. In our study, infections foci, culture positivity rates, isolated microorganisms consistent with the rates reported in the literature.