bluuebunny/crossref_metadata_2025_split huggingface dataset:
TIM-3 Is Highly Expressed On Blast Cells In Patients With Acute Myeloid Leukemia
Authors: Li Caixia , Yu Xiao , Zhu Yibei , Wu Xiaojin , Ma Xiao , Liu Hong , Ye Lu , Ma Chao , Xia Rui , Sun Aining , Ruan Changgeng , Chen Suning , Depei Wu 
Published: October 2019

Abstract
T cell immunoglobulin-3(TIM-3) is known as a negative regulator in anti-tumor immunity through its reaction with TIM-3 ligand, galectin-9. It has been confirmed that TIM-3 is expressed on Th1 cells, dendritic cells, monocytes, macrophages, malignant stem cells and so on. But the expression of TIM-3 and its clinical implications in patients with acute myeloid leukemia(AML) remains unknown. In this study, we sought to determine the expression and clinical implications of TIM-3 in AML. From August 2012 to June 2013, in total of 32 AML patients with sixteen male and sixteen female were enrolled in this study. We collected their peripheral blood before they received any treatment and then obtained their peripheral blood mononuclear cells(PBMC). Monoclonal antibody was added into PBMC and cell population was analyzed by flow cytometry. Blast cells were identified with SSC CD45±and mature lymphocytes with SSC CD45+. The average expression of TIM-3 on blast cells was 43.46%, while on mature lymphocytes was 13.78% (P<0.001). In univariate analysis, the level of expression was not correlated to the percentage of blast cells and there was no difference between each type of AML. Complete remission was similar between different levels of TIM-3 expression(P>0.05). These results demonstrated that TIM-3 was highly expressed on blast cells than on mature cells in AML, which indicated that TIM-3 could be associated with the differentiation of blast cells and a potential marker to detect the tendency of relapse. TIM-3-targeted antitumor therapy presents a perspective possibility.

Disclosures:
No relevant conflicts of interest to declare.
Immunophenotyping Versus Morphological Evaluation Of Fresh and Stabilized Cerebrospinal Fluid As Diagnostic Tool For CNS Involvement In Childhood Acute Lymphoblastic Leukemia
Authors: Sonneveld Edwin , Zwaan Christian M. , van der Sluijs-Gelling Alita J , de Haas Valerie , Pieters Rob , van der Velden Vincent H.J. 
Published: October 2019

Abstract

Introduction
Presence of malignant cells in cerebrospinal fluid (CSF) is a risk factor in pediatric acute lymphoblastic leukemia (ALL). Consequently, these patients receive extra intrathecal treatment. We evaluated the concordance between morphological and flow-cytometric (FCM) results, both on freshly analyzed and on stabilized, overnight transported samples.

Methods
Diagnostic CSF samples of 61 newly diagnosed pediatric ALL patients were divided in two aliquots. One was sent to the local laboratory and processed within a few hours after sampling (lab1). A second aliquot was 1:1 diluted with sterile medium and sent to the reference laboratory (lab2). For all samples, a MGG (May-Grünwald-Giemsa) stained cytocentrifuged slide was morphologically evaluated and two 6-color FCM stainings were performed. Samples were considered positive (CNS2) by MGG if at least one blast was seen and by immunophenotyping if a cluster (≥ 10 events) of ALL cells was detected.

Results
Comparison of morphological data between both laboratories showed concordance in 33 samples (53%). In 20 of the 28 discordant samples only 1 or 2 blasts were reported by a single laboratory. Comparison of FCM data between laboratories was concordant in 58 samples (95%). Three samples (tumor load 15%-18%) were reported positive by one laboratory only; in two of these <100 cells could be acquired per tube. Comparison between FCM and morphology showed discordant results in 25 samples (41%) for lab1 and 19 (31%) in lab2. One discordant case was positive by FCM but negative by morphology, in all others only morphology was reported positive. The latter cases mostly had 1 or 2 blasts reported by morphology, generally not confirmed by the other laboratory.

Conclusions
This study shows that morphological analysis of CSF samples is non-reproducible if only 1 or 2 blasts are suspected. In contrast, FCM analysis of CSF is highly reproducible between fresh and stabilized samples. Although immunophenotyping still seems less sensitive than morphology, discordant samples generally have only 1 or 2 blasts reported by MGG, which is highly irreproducible. Nevertheless, by using a single 8-color tube higher cell numbers may be acquired and the FCM sensitivity may be increased.

Disclosures:
No relevant conflicts of interest to declare.
High Resolution Melting Analyses For Genetic Variants in ARID5B and IKZF1 with Childhood Acute Lymphoblastic Leukemia Susceptibility Loci In Taiwan
Authors: Peng Ching-Tien 
Published: October 2019

Introduction
Childhood acute lymphoblastic leukemia (ALL) is a heterogeneous disease including multiple subtypes, defined on the basis of cell lineage and chromosome anomalies. Previous genome-wide association (GWA) studies report that several ARID5B and IKZF1 single nucleotide polymorphisms (SNPs) are associated with the incidence of ALL. However, high resolution melting analysis (HRM) supplies a faster and more convenient technique to detect SNPs. We applied HRM to detect the SNPs in ARID5B and IKZF1 gene.

Method
Seventy-nine pediatric ALL patients and 80 healthy controls were enrolled. Polymorphic variants of IKZF1 (rs6964823, rs4132601, and rs6944602) and ARID5B (rs7073837, rs10740055, and rs7089424) were detected by HRM method. The SNPs were further analyzed the association with childhood ALL.

Result
We evaluated 6 mutations by PCR amplicons (81 -176 bp) using the 96-well Light Cycler system. The primer detail was listed in Table 1. The melting curve data showed the difference in normalized temperature and we easily and accurately extended application of HRM analysis to genotyping of IKZF1 (Figure 1) and ARID5B (Figure 2) gene variants.
The genotype distribution and the allele frequencies of IKZF1 (rs6964823, rs4132601, and rs6944602) and ARID5B (rs7073837, rs10740055, and rs7089424) gene polymorphisms among cases and controls and their association with the risk of childhood ALL were shown in Table 2. The distribution of genotype rs7073837 in ARID5B was significantly different between the ALL group and the control group (P = 0.046), while the distributions for IKZF1 (rs6964823, rs4132601, and rs6944602) and ARID5B (rs10740055, and rs7089424) were not significantly different. In addition, we analyzed the association for those SNPs with B lineage ALL and found rs7073837 in ARID5B conferred a higher risk for B lineage ALL (odds ratio, OR = 1.70, 95% confidence interval, CI = 1.01-2.87, P = 0.049).

Conclusion
HRM was a practical method to detect SNPs in ARID5B and IKZF1 gene. We determined the rs7073837 in ARID5B was associated with the risk of childhood B lineage ALL.

Disclosures:
No relevant conflicts of interest to declare.
Diagnostic and Prognostic Significance Of Isolated Trisomy 2 In Hematopoietic Malignancies
Authors: Aypar Umut , Waltman Lindsey , Reichard Kaaren , Van Dyke Daniel L. 
Published: October 2019

Abstract
Isolated trisomy 2 in hematopoietic malignancies is rare, having only been reported in eight cases in the literature. Of these cases, the majority are older male patients (7/8) ranging in age from 64 to 84 years. The underlying hematologic malignancies include: myelodysplastic syndrome (MDS), refractory anemia (RA) subtype; MDS, RA with excess blasts (RAEB-II) subtype; MDS, RAEB in transformation (RAEB-t); chronic myelomonocytic leukemia (CMML-t) in transformation; MDS transformed into AML; acute monoblastic and monocytic leukemia (AMoL; FAB M5); and AML in relapse. The molecular pathogenesis and prognostic significance of isolated trisomy 2 remains unknown due to the small number of reported cases. Herein, we report 11 cases of isolated trisomy 2 in hematologic disorders seen in the Mayo Clinic Cytogenetics laboratory from 1996-2012. The majority of patients were older males (7/11) ranging in age from 63 to 93 years. The underlying bone marrow pathologic diagnoses include: hypercellular bone marrow without diagnostic features of malignancy (cases 1 and 2); MDS, refractory cytopenia with multilineage dysplasia (RCMD) subtype (cases 3 and 4); RAEB-1 (cases 5 and 6); long-standing history of primary myelofibrosis now with 7% bone marrow blasts (case 7); acute myeloid leukemia (AML), not otherwise specified (cases 8 and 9); AML with myelodysplasia-related changes (cases 10 and 11). Trisomy 2 has been suggested to represent an age-related phenomenon as it is seen predominantly in older individuals demonstrating this abnormality. Our data suggests that this could be a possible explanation since all of the eleven cases were ages 63 and over. Based on the limited clinical information in our study, it appears that isolated trisomy 2 harbors little prognostic significance and that, rather, the prognostic significance is driven by the underlying pathologic diagnosis. For example, 3 of the 4 AML cases and the case of PMF with increasing bone marrow blasts survived only 7, 8, 6 weeks and 21 weeks post bone marrow biopsy/cytogenetic evaluation, respectively. Although our study only has two cases that lack diagnostic features of malignancy, one of these cases survived 10 years following the identification of the cytogenetic abnormality. Therefore, trisomy 2 as a sole abnormality should not be considered as definitive evidence for MDS in the absence of diagnostic morphological criteria (similar to trisomy 8 and 20q deletion).

Disclosures:
No relevant conflicts of interest to declare.
Acute Lymphoblastic Leukemia Treated With Modified Hyper C-VAD Protocol In Iran
Authors: Jalaeikho Hassan , deylami Ahmad Ahmadzadeh , Keyhani Manoutchehr 
Published: October 2019

Abstract

Background
Relapse and mortality remains high in Acute Lymphoblastic Leukemia (ALL) with reported 5-year survival less than 39%. Bone marrow transplant (BMT) has been offered to some patients; however, 70% of patients do not have a donor-matched sibling and transplant beds are limited in Iran. We treated a cohort of 251 patients by inducing a remission and then treating with Hyper-CVAD rather than treating with Hyper-CVAD at induction and examined survival compared to reports in the literature.

Methods
We conducted a retrospective review of survival of 251 treated with a modified protocol of Hyper-CVAD between 2005 and 2012. The treatment protocol used 4-week induction regimen with Vincristine, Daunorubicin, and Dexamethasone. BCR-ABL positive patients also received daily Imatinib. Intrathecal methotrexate and cytarabine were given to patients with brain involvement. Remission was evaluated by a bone marrow biopsy and aspiration. If patient had T-Cell ALL then we add cyclophosphamide to the induction regimen. Hyper-CVAD treatment was initiated two weeks after last dose of Vincristine. Any patient with brain or bone involvement received radiotherapy post induction. BMT was offered to all BCR-ABL positive patients or those who had a suitable donor. All patients in complete remission received monthly vincristine prednisone for 5 days ,6- mercaptopurine every night and methotrexate every week up to 30 months .Patient with persistent liver enzyme elevation received cyclophosphamide instead of methotrexate.

Result
The mean age was 26 (range 14 to 70). The cohort included patient with T ALL (11%), Burkitt’s type ALL (15%), Pre-B ALL (67%), Pro-B ALL (4%) and BCR-ABL (3%). Sixteen patients died during the first month. Mortality increased to 45 patients at the end of six months. Relapse was the main cause of death. BMT was conducted after complete second remission and suitable patient with BCR-ABL positive patients on 13 occasions but none survived. At 5 years of follow up 129 patients were alive (50.1% survival).

Conclusion
Our patients experienced an improved survival compared to reports in the literature and many did not have complication of radiotherapy. A modified Hyper-CVAD protocol should be the subject of further investigation for the treatment of ALL.

Disclosures:
No relevant conflicts of interest to declare.
Variability In Precursor B ALL Killing With Moxetumomab Pasudotox (CAT-8015) Linked To Differential Binding and Endocytic Trafficking
Authors: Matlawska-Wasowska Ksenia , Nickl Christian K. , Winter Stuart S. , Burke Patricia , LaVallee Theresa , Wilson Bridget S. 
Published: October 2019

Abstract
Precursor-B acute lymphoblastic leukemia (pre-B ALL) is the most common malignancy in children and can be cured in a majority of patients. However, cure remains elusive in approximately 20% of patients for reasons that are not well understood. Moxetumomab pasudotox is one of several CD22-targeting therapies currently under investigation in clinical trials for subjects with B-cell malignancies, including pediatric subjects with pre-B ALL. Moxetumomab pasudotox (MP) is a second-generation immunotoxin composed of disulfide-stabilized, affinity matured VL and VH regions of the mouse anti CD22 monoclonal antibody RFB4 fused to PE38, a truncated form of Pseudomonas exotoxin E. We evaluated in vitro activity of MP against six pre-B ALL cell lines (697, Nalm6, MHH-Call3, RS4;11, SupB15, REH), as well as freshly isolated patient blasts. We found the most sensitive cell line to be Reh, followed by 697, MHH-Call3, and the least sensitive cell lines to be Nalm6 and RS4;11. Toxicity of MP on ALL cell lines and patient blasts was not well-correlated with the number of the CD22 receptors present on the cell surface. However, we found that cleavage of MP by ALL cell lines into active toxin correlated with uptake and inhibition of protein synthesis. Using ALL cell lines, we also demonstrated that binding and internalization of MP/CD22 complexes was correlated with pre-B ALL cell line responses to MP. In addition, the Fv MP/CD22 complexes internalized more slowly than the parent RFB4 antibody/CD22 complexes. In addition to evaluating cell lines, we applied similar assays to 7 patient samples of bone marrow blasts, where we evaluated bound and internalized MP with cellular toxicity up to 72 hours. Our results suggest that some of the heterogeneity observed in in vitro responses to treatment with MP may be related to differences in internalization. Additional studies evaluating intracellular cleavage and trafficking/processing of MP in cell lines and patient blasts is ongoing. These studies, combined with planned in vivo studies evaluating MP antitumor efficacy using ALL cell lines and patient blasts, will provide a more comprehensive picture for differences in ALL response to treatment with MP.
TLaVallee currently affiliated with Kolltan Pharmaceuticals, New Haven, CT, USA; work related to this abstract occurred at MedImmune.

Disclosures:
Burke: MedImmune: Employment. LaVallee:MedImmune: full employee when work was conducted Other.
IPI In Selecting Patients With Diffuse Large B Cell Lymphoma in Rituximab Era
Authors: Genadieva-Stavrik Sonja , Pivkova Alexandra , Stojanoski Zlate , Georgievski Borce 
Published: October 2019

Abstract
Nowadays, goal of treatment approach in diffuse large B cell lymphoma is cure and first step towards it is to achieve complete remission. DLBCL is a potentially curable disease, with curability highly dependent on clinical and biological features. According to the WHO classification of Hematological Malignancies, the entity of DLBCL is characterized by rapidly growing mature B cell tumors with large or relatively large cells and /includes a number of disease variants/entities / encompassing several distinct clinopathologic diseases, several different histologic variants and clinical subtypes. There is no unique treatment for all patients with diffuse large B cell lymphoma. Different subgroup of patients with DLBCL needs different treatment. In the pre-rutuximab era International Prognostic Index (IPI) was considered to be the most important prognostic factor for survival and the strongest indicator for identification of high-risk patients, who are unlikely to be cured with standard chemotherapy. Having in mind that IPI is based on 5 clinical characteristics (age, performance status, stage, extranodal involvement, LDH level) and it is constructed in the pre-rituximab is clear that R-IPI should be tested in rituximab era to provide any information of its validity.
We retrospectively analyzed unselected population of 80 patients with confirmed diagnose of diffuse large B cell lymphoma treated at University hematology department in the period of 2005-2010. All patients were uniformly treated with R-CHOP regiment as initial treatment with curative intent. There were 80 patients with mean age 54, 5 years (15-84), male 35 and female 45. Older than 60 years were 29 patients (36, 25%). More than half of the patients (42) were diagnosed in advanced stage of the disease. We analyzed five prognostic factors: age, performance status, stage, extranodal involvement, LDH level and through the multifactorial analyses we selected two groups of patients. One with 0 to 2 factors as patients with low risk. Patients with more than 3 factors are considered as high risk. There is statistically significant difference in overall survival between two groups with five –years overall survival 70% for low risk patients and 47% for high risk. High-risk patients may be candidates for autologous transplantation as initial treatment, having in mind that in the rituximab era relapses occur very early in the first year and are difficult to be treated.
R-IPI score is significant predictor and should be used for risk stratification of patients with aggressive B-cell lymphoma. However, these findings should be validated prospectively in an independent population of patients.

Disclosures:
No relevant conflicts of interest to declare.
Outcome Of Rapamycin Therapy For Post Transplant- Lymphoproliferative Disorder After Kidney Transplantation: Case Series
Authors: Ashrafi Farzaneh , Shahidi Shahrzad , Ebrahimi Zeinab , Mortazavi Mojgan 
Published: October 2019

Abstract

Background
Post transplant lymphoproliferative disorders (PTLD) , are a complication of chronic immunosuppressive therapy in solid organ transplantation with a high mortality rate. Alternative treatments such as rapamycin have been explored.

Methods
A detailed retrospective analysis was performed according to data collected from thirteen patients with PTLD. At the time of PTLD diagnosis, immunosuppressive therapy was decreased and rapamycin administered. Overall survival and disease free survival of patients and graft survival were determined.

Results
Among 590 kidney transplant recipients, thirteen adult patients with PTLD were included in this study. The mean age of the patients was 42.15 (range: 25-58) years at the time of PTLD diagnosis, and 9 patients were male. Histology was distributed in 9 diffuse large B cell, 1 Malt lymphoma, 1 Burkitt lymphoma, 2 Hodgkin-like PTLD. The response rate to rapamycin alone was 30.8%. The mean overall survival period is 27.4 months with 9 patients still living. In total, 10 patients (76.9%) achieved a complete remission, with functioning graft in 11 (84.6%) patients.

Conclusions
Despite to retrospective and limited number of patients, this study provides promising results regarding the effectiveness of stopping calcineurin inhibitors and switching to rapamycin for patients with PTLD.

Disclosures:
No relevant conflicts of interest to declare.
90Yttrium-Ibritumomab-Tiuxetan As First-Line Therapy Or As Consolidation Treatment In Advanced Stage Follicular Non-Hodgkin Lymphoma: Long-Term Results After a Median Follow-Up Of 61 Months
Authors: Troppan Katharina , Valentin Angelika , Linkesch, MD Werner 
Published: October 2019

Abstract

Purpose
Radioimmunotherapy combines biologic and radiolytic mechanisms to target and destroy tumor cells. 90Y-Ibritumomab-Tiuxetan (90YIT) is a murine anti-CD20 monoclonal antibody engaged for radioimmunotherapeutic targeting of CD20+ lymphoma cells. We report on our long-term follow-up data of 90YIT as first-line or consolidation treatment in advanced stage follicular Non-Hodgkin lymphoma (FL).

Patients & Methods
Between March 2004 and October 2010, forty-seven patients with CD20+ FL grade 1 to 3a in stages II, III, or IV were treated with a single dose of 90Yttrium-Ibritumomab-Tiuxetan (90YIT) at our institution. The median age was 61 years (range 41-83; male 55%) and 77% (n=36) of patients were in an advanced stage of the disease (stage III/IV). 90YIT was administered on an outpatient basis on day 8 after pretreatment with Rituximab (250mg/m²) on day 1. A mean of 1122 MBq (range 680-240) 90YIT was administered. Fourteen patients received 90YIT as first-line therapy, twenty-seven patients were treated with 90YIT after a median of 2 pretreatment courses (range 1-5) as consolidation therapy in remission (15 patients in CR, 12 patients in PR), and six patients showed progressive disease (PD) at time of 90YIT treatment. Median follow-up was 61 months (range 0-111).

Results
After a median follow-up of 61 months (range 0-111 months), 32 patients are still alive, including 21 patients in CR since 90YIT treatment. There was no significant difference concerning PFS and OS between first-line treatment and consolidation treatment, but we found a significant difference, comparing these two groups versus PD (PFS 51 months vs. 48 months vs. 8 months, p<0.023; OS 59 months vs. 71 months vs. 10 months, p<0.002) (figure 1 & 2). Survival rates were 85% (first-line), 67% (consolidation) and 33% (PD), respectively. Patients who maintained a CR after 90YIT treatment, showed significantly longer OS compared to patients with relapse after 90YIT (71 months vs. 52 months, p<0.001). No significant difference in PFS and OS was seen, concerning sex, age, or clinical stage. No unexpected toxicities emerged during long-term follow-up.

Conclusion
90YIT as first-line, as well as consolidation therapy after achieving at least PR, provides a cost-efficient, long progression-free and overall survival in advanced stage FL. No benefit is shown in patients with PD, where we don't recommend 90YIT treatment.

Disclosures:
No relevant conflicts of interest to declare.