bluuebunny/crossref_metadata_2025 huggingface dataset:
Predictors of Emergency Room (ER) Visits and Hospitalizations in Patients with Mantle Cell Lymphoma (MCL) Treated with Chemotherapy
Authors: Feinberg Bruce , Schenkel Brad , McBride Ali , Ellis Lorie , Bhor Menaka , Radtchenko Janna , Lal Lincy S
Published: October 2019

Background: Understanding the predictors of increased healthcare resource utilization is essential for better management of patients with MCL, especially as new agents enter the market. This study evaluated predictors for ER visits and hospitalizations in patients with newly diagnosed and relapsed MCL treated with chemotherapy.

Methods: Using claims data (MORE2 Registry®), patients treated with antineoplastics from August 2009-2013 for MCL were retrospectively identified by ICD-9 codes (200.4, 200.40 - 200.48). Patients with secondary malignancies, pregnancy, and age <18 were excluded. Univariate logistic regression analysis was conducted to determine covariates associated with ER visits and hospitalizations. Results for significant variables were reported as odds ratio/p-value. Odds ratio >1 indicates increase in chance of events.

Results: A total of 449 patients with MCL were identified. Median age at diagnosis was 71 years, 70% were male, 61% had Medicare primary insurance, 32% were treated in the relapsed setting, 50% had ER visits, and 53% had hospitalizations throughout their treatment history. Significant increases in ER visits and hospitalizations were associated with the following factors (OR/p-value): chemotherapy duration (ER: 1.001/.046, hospitalization: 1.001/.01), supportive care (ER: 2.249/.014, hospitalization: 2.56/.004), number of MCL related adverse events (ER: 10.571/<.000, hospitalization: 39.282/<.000), and treatment following relapse (ER: 1.771/.005, hospitalization: 2.012/.001). Significant variables associated with a decrease in ER visits were male gender (0.576/.008) and having commercial insurance (0.548/.009). Age was associated with ER increase (1.024/.024). Patients treated in the Northeast region of the US were more likely to be hospitalized (1.897/.005).

Conclusions: This retrospective study shows that older patients with MCL had a higher likelihood of ER visits, while male patients and patients with commercial insurance had a lower likelihood of ER visits. Regional differences impacted hospitalizations. Adverse events, supportive care, and duration of treatment were associated with increases in hospitalizations and ER visits. These data warrant consideration of age and comorbidity-adjusted treatment in MCL patients eligible for treatment with antineoplastics.

Disclosures

Feinberg: Janssen Scientific Affairs, LLC: Consultancy. Schenkel:Janssen Scientific Affairs, LLC: Employment. McBride:Janssen Scientific Affairs, LLC: Consultancy. Ellis:Janssen Scientific Affairs, LLC: Employment. Bhor:Janssen Scientific Affairs, LLC: Consultancy. Radtchenko:Janssen Scientific Affairs, LLC: Consultancy. Lal:Janssen Scientific Affairs, LLC: Consultancy.
The Prevalence of Anemia in Diabetic Patients with Normal Kidney Function
Authors: Mahjoub Ali R. , Patel Eshan , Ali Sami , Webb Kendal , Kalavar Madhumati
Published: October 2019

Background: Anemia, in patients with diabetes, is commonly associated with impaired renal function secondary to diabetic nephropathy. Many studies have analyzed this association of anemia in diabetic patients and have attributed anemia to reduced renal function. However, there has been no known systematic analysis done to evaluate for the prevalence and predictors of anemia in patients with diabetes in the absence of overt nephropathy.

Objective: This retrospective study is designed to measure the prevalence of anemia in diabetic patients with normal renal function of estimated glomerular filtration rate (EGFR) greater than 90 ml/min/1.73m2 and to analyze the presence of other independent risk factors.

Methods: We conducted a retrospective analysis of 200 medical charts of diabetic patients (age > 18) visiting the outpatient endocrine clinic in our institution between January 2015 and June 2015 to identify the prevalence of anemia with and without diabetic nephropathy and any other associated factors.

Results: The prevalence of anemia (defined by the World Health Organization is a Hemoglobin level of less than 13 mg/dl in men and less than 12 mg/dl in women) in our 200 diabetic patients was 22% (44 out of the 200). Out of the 44 anemic patients, 41% had anemia with normal renal function (18 out of 44), 4 men and 14 women aged between 38-80 years old. From the 18 patients with normal renal function, 5 had iron deficiency anemia and 1 had autoimmune disease, while the remaining 12 patients (27% of anemic patients) did not have any known cause of anemia such as renal insufficiency, infection, chronic inflammatory disease, vitamin B12 or folate deficiencies, hemolysis, or acute/chronic blood loss.

Conclusion: Many studies have highlighted an association between anemia and nephropathy in diabetic patients. This retrospective analysis suggests there is a high prevalence of anemia with unidentified etiology in diabetic population. The exact mechanism of such anemia is not fully understood. It is hypothesized to be likely secondary to direct glucose toxicity to erythrocyte precursors in the bone marrow or from oxidative stress to mature erythrocytes. However, further studies are needed to evaluate the underlying pathophysiology of anemia in this particular setting.

Disclosures

No relevant conflicts of interest to declare.
Congenital Dyserythropoietic Anemia Type 1: A New Variant Pathogenic CDAN1 Mutation
Authors: McDaniel Jenny , Cramer Stuart
Published: October 2019

Introduction:

Congenital dyserythropoietic anemia (CDA) is a rare autosomal recessive condition that results in dyserythropoiesis and iron overload. Bone marrow evaluation in these patients demonstrates distinctive abnormalities in red cell precursors including multinucleated erythroblasts and chromatin bridges. Dysmorphisms such as distal limb abnormalities, skin pigmentation defects, vertebral malformations, and short stature may also be present. Mutations in the CDAN1/codanin-1 gene underlie the majority of CDA type I cases. We describe a previously unreported pathogenic variant.

Case report:

The female fetus of a gravida 2 para 1 woman was noted to have hepatomegaly, cardiomegaly, and elevated middle cerebral artery velocity concerning for severe intrauterine anemia at approximately 20 weeks gestation. The parents had one previous pregnancy that resulted in a stillborn male infant with hydrops fetalis and club foot. Given concern for anemia with this pregnancy, percutaneous umbilical cord blood sampling was performed demonstrating a fetal hematocrit of 9%. This severe fetal anemia was initially thought to be secondary to ABO incompatibility as mother was O- with a positive antibody screen and infant was A+. The fetus required four intrauterine transfusions and was delivered at 34 weeks 6 days via cesarean section due to history of previous cesarean. Exam revealed a phenotypically normal female with APGARs of 9/9 and a birth weight of 2130 grams.

Following delivery the infant had serial blood counts performed over a 6-week period, which noted a steady decrease in her hematocrit to 16%. A transfusion was given, and a bone marrow evaluation revealed a cellular marrow with red cell hyperplasia and dyserythropoiesis. Next generation sequencing through PreventionGenetics was performed revealing a novel CDAN1 alteration.

Results:

The patient was found to be heterozygous for two mutations in trans in the CDAN1 gene: c.2072dupT and c.2093A>T.

Discussion:

We present a patient with severe fetal and infant transfusion dependent anemia who has two novel CDAN1 gene variants not previously described. The sequence variant c.2072dupT is predicted to result in a frameshift and premature protein termination and is expected to be pathogenic. The second variant c.2093A>T is predicted to result in an amino acid substitution (p.Glu698Val). Another amino acid substitution (p.Glu698Lys) was previously reported as pathogenic in an individual with congenital dyserythropoietic anemia. Based upon the clinical picture, morphologic characteristics, and genetic findings, we have concluded that this presentation is consistent with a diagnosis of CDA type I. Through the utilization of improved diagnostic techniques we continue to gain knowledge regarding the molecular underpinnings of CDA type I.

Disclosures

No relevant conflicts of interest to declare.
Serum 25- OH Vitamin D and Parathyroid Hormone Levels in Beta Thalassemia Patients
Authors: Türkkan Emine , Tas Burcu Tufan , Ocak Suheyla
Published: October 2019

Introduction: The survival of the patients with thalassemia has progressively improved with advances in therapy, however, increased survival allowed for several complications of disease. Metabolism of vitamin D affected in patients with thalassemia, due to accumulation of iron in the liver as the skin. The aim of this study is to compare vitamin D and parathyroid hormone (PTH) levels between patients with thalassemia and healthy control group.

Methods: In pediatric hematology clinic, 33 patients (23 male, 10 female) with beta thalassemia major and 33 age-sex matched healthy people as a control group were included. Serum 25- OH Vitamin D levels were defined as normal >30 ng/ml, insufficiency between 20-30 ng/ml and deficiency < 20 ng/ml and PTH levels as normal between 10-65 pg/ml, decreased <10 pg/ml, and increased >65 pg/ml.

Results: Mean age was 23.02+8.18 years old in patient group and 23+ 8.16 in control group. %33.3 of the patients had 25-OH vitamin D insufficiency and %30.3 of had 25-OH vitamin D deficiency. In different studies, the 25-OH vitamin D deficiency found between %12-90, and insufficiency between % 24.7-69.8 of the thalassemic patients. %81.8 of the patients had normal PTH levels, %18.2 decreased and none of the patients were found increased. In literature, there were confluent results about PTH levels in thalassemic patients, some of the studies showed hypoparathyroidism, and some of hyperparathyroidism or normal levels of PTH (Vogiatzi Br J Haematol 2009, Moulas Acta Paediatrica 1997, Merchant Indian J Pediatr 2011). In our study we couldn't show hyperparathyroidism in patient group. Also we found parathyroid hormone levels were significantly lower (p<0.001), while 25-OH vitamin D levels were significantly higher (p<0.05), in patients with thalassemia than in control group. This result was interestingly showed that, normal population in our country may be low levels of vitamin D. So we need more studies about PTH and vitamin D levels of healthy people, not only thalassemic patients in our country.

Disclosures

No relevant conflicts of interest to declare.
Hemoglobinopathy- The Old and New Eras in a South-Eastern Nigerian Tertiary Health Center
Authors: Nwabuko Ogbonna Collins , Okoh Dorathy Adaunwa , Nnoli Martin Anazodo
Published: October 2019

BACKGROUND : Hemoglobinopathy is the commonest genetic defect worldwide and sub-Saharan Africa bears the second largest burden of this disorder. The challenges confronting management of hemoglobinopathy in resource-limited settings in Africa are diagnosis, monitoring and prognostication. The old conventional hemoglobin protein electrophoresis test (HbPE) lacks the capacity to make definitive diagnosis of hemoglobin variants (genotype) of an individual, hence, so many diagnosis of hemoglobinopathy have been missed as a result of this defect. This necessitated the need for more reliable technique for screening, diagnosis, monitoring and evaluation of Hemoglobinopathy (High Performance Liquid Chromatography,(HPLC)).

AIMS : This study aimed to compare the old conventional HbPE and the new chromatographic methods (HPLC) of determining variant Hemoglobin in a south-eastern tertiary health institution in Nigeria.

METHODOLOGY : A one-year prospective study of Eight thousand four hundred and seventy eight (8,478) consecutive patients who presented at the Department of Hematology, Federal Medical Centre, Umuahia for HbPE from January to December 2013 (old era) and seventy (70) patients among them who used HPLC to determine their variant hemoglobin (new era). Biomedical data, electrophoretic and chromatographic patterns of their variant hemoglobin were obtained using the conventional alkaline cellulose acetate HbPE machine and the D-10TM HPLC [Bio-Rad Laboratories] respectively. Statistical analysis was done using SPSS.

RESULT: A total of 8,478 patients made up of 1,505(17.8%) males and 5,013(59.1%) females were seen within the study period. The study included both children ( ≥7months) and adult with majority of them (25%) between age of 20-30 years. Three hemoglobin variants were identified viz: [(AA(6447/76%),AS(1876/22.12%),SS(159/1.88%)] using alkaline cellulose acetate HbPE machine in the old era. In the new era, four Hb variants [AA,AS,SS(5.7%) and SD(1.3%)] were obtained using the HPLC. There was a linear increment in quantitative HbF [(AA(31/37),AS(13/20),SS(0/5) had HbF <1%,while AA(0/37),AS(0/20),SS(2/5) had HbF>10%,(Table 1)] and HbA2 [(AA(45/45),AS(8/20),SS(0/5) and AA(0/45),AS(3/20),SS(2/5) had HbA2<3.5% and >10% respectively,(Table 2)] as you move from AA, AS ,to SS Hb variants. The S-window for all HbSS (4/5) was >70% while that of AS and SD ranged between 40-70%.

CONCLUSION : A critical comparison of the old and new methods of diagnosis of hemoglobinopathy showed that the later (HPLC) was superior to the former (HbPE) in the early detection, diagnosis, quantification, monitoring and prognostication of Hemoglobinopathy. Therefore, HPLC is strongly recommended in the policy guidelines for Hemoglobinopathy screening in health institutions in developing countries such as Nigeria where the prevalence is high.

KEYWORDS : Diagnosis, Hemoglobin variants, HbPE, HPLC, Hemoglobinopathy.

Disclosures

No relevant conflicts of interest to declare.
Molecular Genetics Analysis of Von Williebrand Disease: Studies in Cohort Pakistani Patients
Authors: Ahmed Shariq , Naz Arshi , Yadegari Hamideh , Driesen Julia , Shamsi Tahir , Ahmed Nisar , Tariq Shahla , Amanat Samina Tufail , Razik fazal-E- , Nadeem Mohammad , Oldenburg Johannes
Published: October 2019

Introduction: Von Willebrand disease (VWD) type III is the second most common inherited bleeding disorder in Pakistan. It is caused by severe quantitative deficiency of plasma Von Willebrand factor (VWF). Absence of VWF increases the severity of disease and is caused by homozygous/ compound heterozygous mutations in Von Willebrand factor gene.

Objective: The aim of study is to characterize molecular genetics of Von Willebrand type III in Pakistani population.

Setting: NIBD & BMT Karachi, Chughtais lab, Children's Hospital Lahore, PAEC Islamabad and HMC Peshawar.

Material And Method: In this cohort study of Von Willebrand disease (VWD) type III, Blood samples of 48 unrelated patients of type III VWD were collected in National Institute Of Blood Disease & Bone Marrow Transplant (NIBD) Karachi, Chughtais lab, Children's Hospital Lahore, PAEC Islamabad and HMC Peshawar. Genomic DNA was extracted from peripheral blood by QIAamp DNA Blood mini kit (Qiagen) and Exon specific PCR was done for VWF gene and Direct gene sequenced on automated ABI-3130 Genetic Analyzer (Applied Biosystems). Sequence Variations in VWF were checked on ISTH-SSC VWD homepage (http://www.vwf.group.shef.ac.uk/), Ensemble genome browser (http://www.ensembl.org/), VWFdb hemobase and biobase biological database (http://www.hgmd.cf.ac.uk/ac/index.php). We have adopted the nomenclature for numbering amino acids of Human genome variation society (HGVS). Statistics analysis was done SPSSv17.

Results: Sequence analysis detected mutations in 46 (95.83%) out of 48 samples. VWD type III has led to identification of 28 cases (60.8%) homozygous and 18 (39.1%) were compound heterozygous. We have indentified total 31 Mutations distributed as 17 missense mutations (54%), 7 nonsense mutations (22%) 2 small deletions (6%) , 2 insertion mutations (6%) and 3 splice site mutations (9%).19 of these were newly mutations in this cohort study.. Further method multiplex ligation dependent probe amplification (MLPA) is needed for detection of large deletions in two patients. Nonsense c.3931C>T, p.Q1311*was founder mutation in Pakistani patients.

Conclusion: In cohort study, missense mutations are detected as common in among patients and most of the mutations identified in this cohort were homozygous due to Consanguinity in the family of the patients.

Disclosures

Oldenburg: SOBI: Consultancy.
Granulocyte Colony-Stimulating Factor Inhibits CXCR4/SDF-1 Signaling and Overcomes Stromal-Mediated Drug Resistance in Acute Myeloid Leukemia Via Mir-146a
Authors: Zhong Hua , Xu Lan , Li Xin , Sheng Xian-fu , Chen Fang-yuan , Hu Jiong
Published: October 2019

CAG regimen was widely used in the clinical treatment of acute myeloid leukemia (AML). However, the mechanisms of G-CSF in the CAG regimen remain unknown. For the purpose of better elucidating the function of G-CSF, we evidenced that G-CSF could enhance HL60 and primary leukemia cells proliferation in vitro. Meanwhile, transwell migration experiments demonstrated that G-CSF, similar as the CXCR4 antagonist AMD3100, could remarkably inhibit the chemotaxis of HL60 cells induced by the chemokines released from marrow stromal cells (Fig 1). qRT-PCR and Western blotting results showed that the expression of miR-146a was up-regulated after G-CSF treatment, while the expression levels of CXCR4 and smad4 were down-regulated (Fig 2). CXCR4 and Smad4 expression levels in miR-146a over expression lentivirus infected HL60 cells were significantly decreased, which manifested the direct or indirect targeted relationship between miR-146a and CXCR4/Smad4. Our qRT-PCR and Western blotting results also showed an involvement of NF-KB in G-CSF induced up-regulation of miR-146a in AML cells. G-CSF activated NF-KB in the cells. Activated NF-KB induced the up-regulation of miR-146a expression. Sanguinarine, an inhibitor of NF-KB significantly inhibited miR-146a expression. We further demonstrated the involvement of NF-KB in the regulation of G-CSF in CXCR4 and Smad4 expression (Fig 3). Our study demonstrated that G-CSF not only could induce resting leukemia cells into proliferation cell cycle, but also could inhibit chemotaxis of leukemia cells. We elucidated the mechanism of G-CSF/NF-KB/miR-146a/CXCR4 signaling pathway in CAG treatment of AML. The expression levels of MiR-146a /CXCR4 /Smad4 may be selected as the clinical markers for CAG protocol choosing.

Disclosures

No relevant conflicts of interest to declare.
Necroptosis of a Small Subset of Hematopoietic Progenitors Induces Autoimmune Bone Marrow Failure
Authors: Xin Junping , Allen Ni , Gutierrez Rafael , Chen Haiyan , Li Jing , Cannova Joseph , Ng Grace , Schmidt Rachel , Wei Wei , Breslin Peter , Kuo Paul C , Stiff Patrick J. , Zhang Jiwang
Published: October 2019

Acquired aplastic anemia (AAA) is an autoimmune-mediated bone marrow failure (BMF) syndrome. Cryptic clonal genetic lesions were commonly detected in a small subset of hematopoietic stem/progenitor cells (HSPCs) in most patients' BM samples. The mechanism by which the autoimmune reaction is initiated is unknown. Whether and how these cryptic clonal genetic lesions might cause autoimmune BMF have not yet been determined. We found that mice with spontaneous deletion of the TGFβ-activated kinase-1 (Tak1) gene in a small subset of HSPCs (1-3%) developed BMF which resembled the clinical manifestations of AAA patients. BMF in such mice could be reversed by depletion of CD4+ T lymphocytes or treatment with IFN-γ, suggesting a Th1 cell-mediated autoimmune mechanism. Interestingly, the disease onset and progression of BMF in such mice were significantly accelerated by inactivation of TNF-α signaling, indicating that TNF-α might restrict the progression of autoimmune BMF. Furthermore, we determined that the necroptosis of a small subset of hematopoietic cells is the cause of autoimmune BMF because such BMF can be completely prevented by deletion of Rip3, a key necroptotic mediator. Our study suggested that the necroptosis of a small subset of hematopoietic cells induces autoimmune BMF, and that elevated TNF-α restricts the progression of such autoimmune BMF. We believe that, in addition to inhibiting T-cell-mediated autoimmune reactions to induce disease remission, repression of the necroptosis of mutant HSPCs might be necessary to prevent disease relapse and progression of autoimmune BM failure.

Disclosures

Stiff: Gilead: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Fate Therapeutics: Research Funding; Plasmacyclics: Consultancy, Honoraria, Research Funding; Eisai: Research Funding.
Utility of Telomere in Diagnosis of Bone Marrow Failure Syndromes
Authors: Abdel-ghaffar Hasan Ahmed , Zaghloul Hosam , El-Waseef Ahmed , El-Naggar Mohamed , Mabed Mohamed , Darwish Ahmad , Al-Dahshan Zainab
Published: October 2019

Background and aim of the work: Bone marrow failure syndromes (BMFS) includes inherited and acquired conditions. Inherited bone marrow failure includes a number of syndromes; with Fanconi anemia (FA) being the most common one of them. Telomeres are eroded with cell division, but in hematopoietic stem cell, maintenance of their length is mediated by telomerase. Short telomeres can result in instability of cell function where diseases occur. Bone Marrow Failure might be developed due to low telomerase activity or short telomeres. Our study is aiming to evaluate the utility of Real Time Quantitative-Polymerase Chain Reaction (RT-qPCR) in measuring the relative telomere length and its significance in diagnosis and prognosis of patients with BMFS.

Materials and methods: The study includes 3 groups: A group of congenital BMF (29 patients), a group of acquired BMF (10 patients) and a third control group (15 cases). The relative telomere length is evaluated for them using RT-qPCR.

Results: We have found that there is a significant difference in relative telomere length between congenital group and controls (p=0.001), also a significant difference between acquired group and controls (p= 0.029). However, there is no significant difference between congenital and acquired groups (p= 0.479). There is no significant correlation between the telomere length and the overall survival or prognosis of the patients of BMFS.

Conclusion: We conclude that the telomere length is significantly altered in patients with BMFS whether being congenital or acquired compared to the control group.

Disclosures

No relevant conflicts of interest to declare.
The Herbicide Isoproturon Induces Activation-Induced Cytidine Deaminase Expression in Germinal Center B Cells
Authors: Leeman-Neill Rebecca J , Johnson Daniel E , Swerdlow Steven H
Published: October 2019

Several epidemiologic studies have demonstrated an increased risk of non-Hodgkin B cell lymphoma with exposure to pesticides, including herbicides, fungicides and insecticides. Few studies have specifically demonstrated an increased risk for follicular lymphoma in individuals exposed to pesticides. The molecular mechanisms of these associations have not been fully investigated. Activation-induced cytidine deaminase (AID), which physiologically mediates somatic hypermutation in germinal center B cells, has been found to have off-target effects that play an important role in oncogenic mutagenesis driving germinal center type B cell lymphomas. Elevated levels of AID among peripheral blood mononuclear cells has been found to be associated with higher numbers of circulating follicular lymphoma-like cells in individuals exposed to pesticides. Increased AID expression and/or activity represents a possible mechanistic link between pesticide exposure and lymphomagenesis.

In order to test the hypothesis that pesticides might lead to an increased risk of germinal center neoplasia by increasing AID levels, four pesticides including isoproturon (a phenylurea herbicide), chlorpyrifos (an organophosphate insecticide), DDT (an organochlorine insecticide), and lindane (an organochlorine insecticide), were screened for their ability to increase AID expression in germinal center type B cells (Ramos and Raji, Burkitt lymphoma cell lines). After 48 hours of treatment with concentrations ranging from 50-200 μM, RNA was extracted, reverse transcribed and cDNA subject to SYBR green Realtime PCR amplification of AID.

AID was found to be expressed, at low levels, in untreated Ramos and Raji cells, compared to acute myeloid leukemia cell lines HL60 and U937, which served as negative controls showing no AID expression. Isoproturon treatment resulted in a dose dependent, up to 6-fold, increase in AID in Ramos cells. A smaller, up to 1.9 fold increase was seen in Raji cells. None of the other pesticide treatments resulted in increased expression of AID (Fig. 1).

The findings demonstrate that AID expression is induced by isoproturon, a member of the class of phenylurea herbicides which is among the most commonly used herbicides worldwide and generally considered to be relatively safe for humans. These results support a possible role for off-target AID activity in pesticide-exposure related lymphomagenesis. Future studies will investigate the mechanism by which AID is upregulated andwhether or not there is induction of oncogenic mutagenesis in germinal center B cells exposed to phenylurea herbicides.

Disclosures

No relevant conflicts of interest to declare.
Mir-155 Enhances B-Cell Lymphoma Growth By Targeting TBRG1
Authors: Kluiver Joost , Slezak-Prochazka Izabella , Winkle Melanie , Visser Lydia , Diepstra Arjan , Kroesen Bart-Jan , Van den Berg Anke
Published: October 2019

Several studies have indicated an important role for miR-155 in the pathogenesis of B-cell lymphoma. Highly elevated levels of miR-155 were indeed observed in most B-cell lymphomas with the exception of Burkitt lymphoma (BL). However, the molecular mechanisms that underlie the oncogenic role of miR-155 in B-cell lymphoma are not well understood. To identify the miR-155 targets relevant for B-cell lymphoma, we performed RNA immunoprecipitation of Argonaute 2 in Hodgkin lymphoma (HL) cells upon miR-155 inhibition and in BL cells upon ectopic expression of miR-155. We identified 54 miR-155-specific target genes in BL cells and confirmed miR-155 targeting of DET1, TBRG1 (NIAM1), TRIM32, HOMEZ, PSIP1 and JARID2. Five of these targets are also regulated by endogenous miR-155 in HL cells. Both overexpression of miR-155 and inhibition of expression of the miR-155 target gene TBRG1 increased proliferation of BL cells. In primary B-cell lymphoma TBRG1-positive cases have significant lower levels of miR-155 as compared to TBRG1-negative cases, suggesting that TBRG1 is also regulated by miR-155 in primary B-cell lymphoma. Thus, our data indicate that miR-155 plays an oncogenic role in B-cell lymphoma by targeting the tumor suppressor TBRG1.

Disclosures

No relevant conflicts of interest to declare.
Targeting Reptin Function in Acute Myeloid Leukaemia
Authors: Armenteros-Monterroso Elena , Zhao Lu , de Boer Jasper , Williams Owen
Published: October 2019

Acute myeloid leukaemia (AML) is characterized by the rapid growth of immature white blood cells, which accumulate in the bone marrow and are not able to differentiate into normal functioning cells. Despite recent advances in AML therapy, cytogenetically defined subgroups with poor prognosis are still prevalent. Chromosomal translocations, which encode abnormal fusion proteins, are common in patients with AML, and the MLL (Mixed Lineage Leukaemia) locus is the most frequently rearranged in paediatric AML. Previous studies in our laboratory used global gene expression analysis in conditionally immortalized MLL-rearranged mouse myeloid cells to demonstrate that the Reptin gene was positively regulated by MLL-fusion genes. Reptin (also known as RUVBL2), together with its related family member Pontin (also known as RUVBL1), functions as part of multi-protein complexes involved in chromatin remodelling, DNA repair, regulation of transcription and ribonucleoprotein assembly. Further work in our laboratory found Reptin to be essential for sustaining the hyperproliferative state and clonogenic potential, as well as suppressing apoptosis, of human AML cells, both MLL-rearranged and non-MLL rearranged. Here, we present our recent data, investigating the transcriptional pathways regulated by Reptin in order to identify clinically approved drugs that can modulate these pathways, and using xenotransplantation assays to establish the efficacy of targeting Reptin in vivo. Our preliminary results indicate that Reptin regulates the function of the oncoprotein c-MYC in human AML cell lines and represents an exciting novel candidate target for the therapy of human AML.

Disclosures

No relevant conflicts of interest to declare.
Clinical Significance of Soluble Interleukin-2 Receptor in Patients with Acute Leukemia
Authors: Wang Dongjiao , Wang Jujuan , Qiu Hongxia , Duan Limin , Tian Tian
Published: October 2019

Objective: Investigate the expression level and clinical significance of serum soluble interleukin-2 receptor (sIL-2R, sCD25) in patients with acute leukemia.

Methods: Serum sCD25 level were measured using enzyme linked immunosorbent assays (ELISA) in 97 acute leukemia patients and 10 healthy contrlols. Clinical and laboratory features, including bone marrow cellularity, white blood cell count (WBC), platelets (PLT), lactate dehydrogenase (LDH), serum ferritin (SF), erythrocyte sedimentation rate (ESR), as well as overall survival (OS) data were collected.

Results: (1) Serum sCD25 level of the newly diagnosed leukemia group was significantly higher than that of the control group (P<0.0001). (2) Among the newly diagnosed AML patients, serum sCD25 level of the M3 group was significantly lower than that of the M2 or non-M2/M3 group (P<0.05). In addition, serum sCD25 level of the low/intermediate risk (AML) or standard risk (ALL) group was lower than that of the high risk group (P<0.05). (3) Serum sCD25 level of the complete remission (CR) group was significantly lower than that of the newly diagnosed group (P<0.002). However, no significant decrease was found in serum sCD25 level of the relapsed/refractory group compared to that of the newly diagnosed group. (4) Serum sCD25 level in newly diagnosed patients was positively correlated with peripheral WBC, LDH and SF. (5) Furthermore, although OS of the low sCD25 level group (sCD25<2000pg/ml) was not significantly different compared to the intermediate sCD25 level group (2000≤sCD25≤4000pg/ml) (P=0.532), both that of the low or intermediate sCD25 level group were significantly superior to that of the high sCD25 level group (sCD25>4000pg/ml) (P<0.05).

Conclusion: Serum sCD25 levels have important clinical significance in evaluating disease activity, treatment outcomes and prognosis in patients with acute leukemia.

Disclosures

No relevant conflicts of interest to declare.
Secondary Central Nervous System (CNS) Involvement in Patients Diagnosed with Diffuse Large B-Cell Lymphoma (DLBCL) during the First Line R-CHOP Treatment and after the End of Treatment
Authors: Romejko-Jarosinska Joanna , Osowiecki Michal , Ostrowska Beata , Kotarska Martyna , Domanska-Czyz Katarzyna , Szymanski Marcin , Targonski Lukasz , Borawska Anna , Druzd-Sitek Agnieszka , Paszkiewicz-Kozik Ewa , Poplawska Lidia , Rymkiewicz Grzegorz , Walewski Jan
Published: October 2019

Background: Secondary central nervous system (CNS) involvement is an unfavorable risk factor with an impact on overall survival (OS) in malignant lymphoma.

Methods: We conducted a retrospective analysis of secondary CNS involvement in patients diagnosed with Diffuse Large B-Cell lymphoma (DLBCL) on the first line treatment and after the end of treatment. We collected data on 361 patients diagnosed with DLBCL.

Results: The median age (range) was 66 (17-91) years. All patients received first-line R-CHOP21 (rituximab, cyclophosphamide, vincristine, doxorubicin, prednisone) between 2006-2011. Patients with primary involvement of testis, nasopharynx, orbit and CNS received CNS prophylaxis with 15 mg methotrexate intrathecally (IT). Secondary CNS involvement was confirmed in 18 (4.9%) patients which stands for 24.6% (18/73) patients with relapsed lymphoma. Median time from first R-CHOP to lymphoma relapse was 10 months (range 3-33). CNS involvement in first 12 months of treatment was 3.9% (95% CI: 1.8%, 5.8%). Median (range) OS from diagnosis of CNS involvement was 3 (3-79) months. Clinical stage III/IV, IPI 4, breast, 2 or more extranodal sites and NCCN-IPI unfavorable site involvement increased the risk of CNS involvement. Three patients who had received methotrexate IT prophylaxis had CNS involvement at relapse. No patient with primary testis involvement had CNS relapse.

Conclusion: Less than 5% of patients had secondary CNS involvement on first line treatment and after end of treatment. Advanced stage, high-risk IPI, 2 or more extranodal sites of involvement increased the risk of CNS involvement after first-line treatment for DLBCL. CNS prophylaxis appears effective in patients with primary testicular lymphoma

Disclosures

Walewski: Karyopharm: Consultancy; Roche: Consultancy, Honoraria, Other: travel, accommodation, Research Funding; Celgene: Honoraria, Other: travel, accommodation, Research Funding; Gilead: Consultancy, Honoraria, Other: travel, accommodation; Takeda: Consultancy, Honoraria, Other; Ariad: Consultancy; Janssen-Cilag: Consultancy; Mundipharma: Consultancy, Honoraria, Research Funding; Genetics: Other: travel, accommodation; Teva: Consultancy, Honoraria; Seattle: Other: travel, accommodation; GSK/Novartis: Research Funding; Boehringer Ingelheim: Consultancy; Sanofi: Honoraria, Other: travel, accommodation; Servier: Consultancy.
Characteristics of the TCR Vbeta Repertoire and Identical Clonally Expanded T Cells in Chronic Myeloid Leukemia Patients in Advanced Phase with ABL Mutations
Authors: Xu Ling , Lu Yuhong , Lai Jing , Yu Wei , Jin Zhenyi , Xu Yan , Chen Jie , Zha Xianfeng , Chen Shaohua , Yang Lijian , Li Yangqiu
Published: October 2019

Abstract

Tumor specific or related antigen cytotoxic lymphocyte (CTL) have been identified in chronic myeloid leukemia patients, however, whether they are constituted by specific type of T cell receptor chains has not been illustrated so far. Previous studies have reported abnormal TCR repertoires and clonally expanded TCR Vβ T cells in chronic myeloid leukemia in chronic phase (CP-CML). In this study, we investigated the distribution and clonality of the TCR Vβ repertoire in 5 CML patients in blast crisis (BC-CML) and one in acceleration phase (AP-CML) with ABL kinase domain mutations (KDMs) including T315I, E255K, F317L+S417Y, Y-253F and L387M+T-315A. Examination of TCR Vβ expression and clonality was performed by reverse transcription-polymerase chain reaction (RT-PCR) combined with GeneScan analysis. Significantly skewed TCR Vβ repertoires were observed in those patients, and 4 to 8 oligoclonally expanded TCR Vβ subfamilies could be identified in each sample, which distributed in 15/24 different subfamilies (TCR Vβ4, Vβ5, Vβ6, β8, Vβ9, Vβ10, Vβ15, Vβ16, Vβ17, Vβ18, Vβ19, Vβ21, Vβ22, Vβ23, Vβ24). Intriguingly, a relatively highly expanded Vβ9 clone with the same length as CDR3 (139 bp) was found in all three CML patients in lymphoid blast crisis (LBC-CML) who had different KDMs, but the clone was not detected in the other two CML patient in myeloid blast crisis (MBC-CML) or the one CML patients in accelerated phase. In conclusion, restricted TCR Vβ repertoire expression and decreased clone complexity was a general phenomenon in the BC-CML patients with different KDMs, indicating the T-cell immunodeficiency status of these patients, and clonally expanded Vβ9 T cell clones may represent a specific immune response to leukemia-associated antigens in LBC-CML patients.

Disclosures

Li: The Foundation for High-level Talents in Higher Education of Guangdong, China ([2013]246-54),and the Guangzhou Science and Technology Project Foundation (201510010211): Research Funding; National Natural Science Foundation of China (81270604, U1301226, and 81400109), the Guangdong Natural Science Foundation (S2013040016151 and S2013020012863): Research Funding.
A Phase II, Open-Label Pilot Study to Evaluate the Hematopoietic Stem Cell Mobilization of TG-0054 Combined with G-CSF in 12 Patients with Multiple Myeloma, Non-Hodgkin Lymphoma or Hodgkin Lymphoma - an Interim Analysis
Authors: Setia Gayatri , Hagog Nabil , Jalilizeinali Bita , Funkhouser Sharon , Pierzchanowski Loretta , Lan Fengshuo , Gabig Theodore G. , Kiner-Strachan Bonnie , Kelleher Karen , Hsu Ming-Chu , Chang Li-Wen , Schuster Michael W.
Published: October 2019

Background: TG-0054 (burixafor) is a potent and selective antagonist of human chemokine receptor CXCR4 that inhibits the binding of stromal-derived factor 1 (SDF-1). Interruption of the CXCR4/SDF-1 interaction prevents sequestration of CD34+ stem cells to the bone marrow and subsequently mobilizes these cells into the peripheral blood within 1 to 3 hours of drug administration.

Materials and Methods: An open-label, phase II pilot trial was conducted in patients with multiple myeloma (MM), non-Hodgkin's lymphoma (NHL), or Hodgkin's lymphoma (HL) to evaluate the safety and stem cell mobilization of TG-0054 in combination with G-CSF. We planned to treat twelve patients with subcutaneous injections of 10 µg/kg/day G-CSF in the afternoon for 4 days. On the morning of Day 5, patients received 3.14 mg/kg TG-0054 and underwent large volume (18-24L) leukapheresis approximately 2 hours post-drug infusion. Patients were allowed by protocol to undergo leukapheresis for 1-5 days to obtain the predetermined target of ≥5.0 x 106 CD34+ cells/kg. 9 of 12 patients have been treated thus far with a plan to treat 3 additional patients.

Results: A planned interim analysis revealed that6 of the 9 patients treated thus far collected more than 10 x 106 CD34+ cells/kg in 1 leukapheresis session. 2 patients required 2 days to achieve the study endpoint, and 1 outlier patient who had received Revlimid only 1 week prior to peripheral blood CD34 analysis failed to mobilize stem cells until he was allowed 2 more weeks to recover from his Revlimid treatment. Burixafor was well tolerated, and there were no adverse events that were attributed to the drug. All of the patients engrafted promptly after melphalan (7 patients) or BEAM (2 patients) conditioning regimens.

Conclusion: Burixafor in combination with G-CSF is a potent and well-tolerated mobilizer of stem cells into the peripheral blood, and with the exception of 1 outlier, was able to mobilize >5.0 x 106 CD34+ cells/kg in 1-2 leukapheresis sessions in all patients treated thus far (median 1 day). This contrasts with our historical controls that required a median of 2-3 days to achieve a collection of ≥5.0 x 106 CD34+ cells/kg. A total of 12 patients will be treated on this pilot study. These encouraging results warrant the further testing of this drug in a larger randomized clinical trial.

Disclosures

Hsu: Taigen Biotechnology: Employment. Chang:Taigen Biotechnology: Employment. Schuster:Taigen Biotechnology: Research Funding.
Prognostic Implications of Abdominal Computed Tomography at Diagnosis in Patients with Polycythemia Vera or Essential Thrombocythemia
Authors: Song Ik Chan , Lee Jeong Eun , Choi Yoon Seok , Moon Ji Young , Lee Hyo Jin , Yun Hwan Jung , Kim Samyong , Baek Seung Woo , Shin Kyung Sook , Jo Deog-Yeon
Published: October 2019

Background: To our knowledge, no reports have examined the clinical significance of splenomegaly measured using computed tomography (CT) in patients with polycythemia vera (PV) or essential thrombocythemia (ET). This study retrospectively analyzed abdominal CT in PV and ET patients to determine the prognostic role of splenomegaly on CT at diagnosis.

Methods: This study enrolled patients who were newly diagnosed with PV or ET between 2005 and 2014 at Chungnam National University Hospital. Spleen volume was estimated by measuring the caudocranial dimension and maximum size and thickness in the axial plane on cross-sectional images (Prassopoulos et al. Eur Radiol 1997;7(2):246-8).

Results: In total, 46 patients were diagnosed with PV and 73 with ET; abdominal CT was performed at diagnosis in 38 (82.6%) PV patients and 45 (61.6%) ET patients. The International Working Group for Myeloproliferative Neorplams Research and Treament (IWG-MRT) risk score and International Prognostic Score for ET (IPSET) were well applied to these patients group. In the PV group, there were no significant differences in clinical features or laboratory findings between patients who did or did not undergo CT. In the ET group, patients who underwent abdominal CT had lower hemoglobin and hematocrit levels, and were less likely to have a history of thrombosis than those who did not. Splenomegaly was observed in 29 (73.7%) patients with PV and 18 (40.0%) patients with ET. Splenomegaly greater than twice the normal value was observed in 11 (28.9%) PV patients and 4 (8.9%) ET patients. In the PV group, patients with splenomegaly on CT had significantly higher leukocyte and lactate dehydrogenase (LDH) levels than patients without splenomegaly. Splenomegaly more than twice the normal value were not observed in PV patients over 67 years old; in younger patients, PV patients with splenomegaly greater than twice the normal value had lower overall survival than those with smaller spleens (p = 0.02). In the ET group, patients with splenomegaly on CT had higher hemoglobin, hematocrit, leukocyte, and LDH levels than did patients without splenomegaly, but there was no difference in their overall survival (p = 0.643).

Conclusion: These results indicate that splenomegaly measured by abdominal CT might be useful for predicting prognosis in patients with PV.

Disclosures

Jo: Alexion Pharmaceuticals: Research Funding.
LOXL2 Highly-Expressed Induce the Transition of Stromal Cells into Cancer-Associated Fibroblasts Which Maybe Involve in Myeloproliferative Neoplasms Progession
Authors: Xu Na , Li Yuling , Zhou Xuan , Li Lin , Lu Qisi , Liu Qifa , Xiaoli Liu
Published: October 2019

Backgroud and objective: Myeloproliferative neoplasms (MPNs) are malignant disorders by proliferation of one of the myeloid lineages and characteristically show an increase in bone marrow reticulin reticulin-fibrosis.Lysyl oxidases like-2(LOXL2) is copper-dependent amine oxidases that play a critical role in the biogenesis of connective tissue by crosslinking extracellular matrix proteins, collagen and elastin,and Cancer associated-fibroblasts (CAFs) are major mediators in tumor microenvironment. Studies found that loxl2 stimulate CAFs grouth solid tumor,and the expression of LOXL2 is increased in MPN patients,espessionly in PMF patients.Here, we want to evaluate whether the expression of higher LOXL2 associated to CAFs during various MPN progression.

Patients and methods: We compared normal bone marrows and those from patients with chronic myeloid leukemia(CML)(include CML-CP n=20,CML-BC n=13),polycythemia vera(PV)(n=18), essential thrombocythemia(ET) (n=23), and primary myelofibrosis (PMF) (n=8). We detected α-smooth actin and reticulin protein by immunohistochemical staining, examined LOXL2 expression by western blot in bone marrow and ELIZA kit in serum.

Results: LOXL2 was not detected in normal bone marrows and serum.The level of LOXL2 gene is over expressed in PMF (p<0.01) and CML-BC (p=0.02). In other MPNs a differential pattern of expression were statistically significant (P< 0.010).The level of LOXL2 expression associated with reticulin protein expression in bone marrow, especially if reticulin protein expressed higher than 2+(p=0.01).

We detected α-smooth actin positive stromal cells in CML-BC and PMF patients,and the level of LOXL2 expression is related to α-smooth actin positive stromal cells(p<0.05).we also detected α-smooth actin after co-cultured mesenchymal stem cell(MSCs) with sLOXL2 for 96 hour.

Conclusion: Higher level of LOXL2 could be promote MPN progression by modulating several functions of surrounding stromal cells which acquire features of cancer-associated fibroblasts involved in the pathogenesis of MPN. These findings maybe used as the basis for future targeted therapy directed against MPN progression.

Disclosures

No relevant conflicts of interest to declare.
Epidemiology Data of Patients with Chronic Lymphocytic Leukemia in West Central Mexico
Authors: Campos-Cabrera Virgina , Campos-Cabrera Gregorio , Campos-Cabrera Salvador , Rivera-Trujillo Alicia , Hernandez-Rodriguez Sonia , Gomez-Guijosa Miguel-Angel , Mora-Torres Maria , Pedraza-Colin Maria-Luisa , Cuin-Macedo Sergio , Pita-Ramirez Luis , Campos-Villagomez Jose-Luis
Published: October 2019

Background: chronic lymphocytic leukemia (CLL) is a rare disease in Mexican mestizos (Br J Haematol 2015;169:909-911 and Int J Hematol 1999;69:253-255). No significant data on epidemiology is available.

Methods: epidemiological data from samples referred to Laboratorios Fatima de Michoacan for flow cytometry immunophenotyping for neoplastic hematological disease.

Results: 229 samples were received, 52 were diagnosed as CLL (22.7 %). Male 32 and female 20, ratio 1.6 a 1. Age from 33 to 89 years, average 66; 31 to 40 one, 41 to 50 two, 51 to 60 eleven, 61 to 70 twenty four, 71 to 80 ten, more than 81 four. Expression of CD 38 and ZAP-70 in three; only CD38 in 2, only ZAP-70 in three.

Conclusions: similar results in male female ratio and age of presentation are noted as compared with international data. Low frequency of expression in CD38 and ZAP-70 may be due pre-analytic phase in the management of the sample. As a regional group we are trying to have epidemiology data in non-malignant and malignant hematological diseases to form specific protocol treatments.

Figure 1. Figure 1.

Disclosures

No relevant conflicts of interest to declare.