bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene Expression Levels Of Imatinib Transporters and Molecular Response To Imatinib Therapy In Chronic Myeloid Leukemia Patients
Authors: Malhotra Hemant , Sharma Pratibha , Bhargava Shipra , Malhotra Bharti , Kumar Madhu 
Published: October 2019

Abstract
Imatinib mesylate (IM) is the standard first-line treatment for most CML patients. After an initial response, approximately 30 to 40% patients develop resistance to the drug. Various mechanisms of resistance to Imatinib therapy have been identified. One of the mechanisms proposed is varying expression levels of the drug transporters. In the present study, we determined the relative expression levels of Imatinib transporter genes (hOCT1, ABCB1, ABCG2) in CML patients by quantitative real time polymerase chain reaction (qRT-PCR) and correlated these levels with molecular response.
One hundred and ten CML patients were considered for gene expression analysis study for hOCT1 gene and eighty seven CML patients were considered for gene expression analysis study for ABCB1 and ABCG2 genes. CML patients who were on IM therapy for more than 2 years were divided into two groups: Responders: patients who achieve a Complete Molecular response (CMR) or a Major Molecular Response (MMR) [bcr/abl: abl ratio <1% as assessed by RQ-PCR] and Non-responders: those without CMR or MMR (bcr/abl: abl ratio =/> 1% as assessed by RQ-PCR). The relative transcript expression levels of the three genes were compared between responders and non-responders. No significant difference in the expression levels of hOCT1, ABCB1 and ABCG2 was found between the two categories - responders versus non-responders (p value > 0.05). The median transcript expression levels of hOCT1, ABCB1 and ABCG2 genes in responders were 30.63, 10.14 and 0.59 versus 40.13, 8.34 and 0.53 in non-responders, respectively.
We conclude that, in our study, the mRNA expression levels of IM transporter genes did no correlate with molecular response in CML patients.

Disclosures:
No relevant conflicts of interest to declare.
Is Superinstability Of Karyotype Of Acute Myeloid Leukemia “Relic Radiation From Big Bang” Of Chromosome Homeostasis On MDS Stage?
Authors: Luchinin Alexander S. , Turkina Anna G. , Ovsepyan Vanik A. 
Published: October 2019

Abstract

Introduction
In some cases of the cytogenetic analysis patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) there are increase frequency non-clonal disorders (“cytogenetic noise”) in combination with complex (≥ 3 chromosomal aberration) clonal disorders. It is not infrequently manifested in the form of superinstability of the karyotype. In this case every aberrant cell is genetic different from each other. It is obvious that super unstable karyotype has a poor prognosis even more than complex clonal disorders, since due to the high genetic instability is a strong possibility of mutations that cause resistance to chemotherapy. In other words, the high level of “cytogenetic noise” on background of complex clonal disorders can be used as a marker of highly aggressive course of AML and MDS. The aim of our study was to determine the effect of superinstability of the karyotype on the current and prognosis of AML and MDS.

Methods
Thus, 157 patients with cytogenetic survey from register of AML and MDS by Kirov Research Institute of Heamatology were included in our research. They are 73 men, 84 women have the age from 21 to 81 (Me 55) years. Among them 34 patients have MDS and 123 – AML excluding promyelocytic leukemia. Chromosomal aberration were determined from bone marrow aspirate by standard cytogenetic method (GTG-method). Was evaluated at least 20 metaphase cells.

Results
Among MDS patients the prevalence of superinstability of the karyotype was 29%, while among AML – only 4%, χ2=16.9, p<0.0001. In MDS group 2 patients (20%) are RAEB-1, 7 (70%) – RAEB-2, 1 (10%) – unspecified MDS. In AML group 2 patients (40%) are M2 FAB, 1 (20%) – M4 FAB, 2 (40%) - unspecified AML. Given that this type of cytogenetic of high instability is a characteristic feature of MDS, we can suppose, that AML with such instability always have the preliminary MDS stage with cell superinstability of the karyotype. In other words, the superinstability of the karyotype in AML can be regarded as “relic radiation from Big Bang” of chromosome homeostasis, which occurred at the preliminary MDS stage. The median of overall survival among all these patients treated by standard chemotherapy was 3 month, maximum survival – 16 month. The median of overall survival in AML patients was 1 month, MDS – 3.5 months. All patients were died.

Conclusion
A chromosomal superinstability of tumor cells that greatly enhances the aggressiveness of the current AML and MDS, leading to chemotherapy resistance and dramatically reduces the overall survival patients. Superinstability of the karyotype determines the group of patients untreatable by standard chemotherapy. The allogeneic bone marrow transplantation need in these cases.

Disclosures:
No relevant conflicts of interest to declare.
Outcome Of Patients With Acute Myeloid Leukemia/High Risk MDS According To The Kidney Function
Authors: Malkawi Ahmed , Anand Ankit , Al-Ameri Ali , Abdelfatah Mohamed , Kanaan Zeyad , Haller Nairmeen 
Published: October 2019

Abstract

Background
Acute renal failure or injury is a common complication of treatment of patients with acute myelogenous leukemia (AML) or high risk MDS, but the effect of renal function of patients who have acute myeloid leukemia/high risk MDS is not clearly highlighted as a predictor of survival, to the best of our knowledge this issue has not been studied in depth before.

Aim
study the effect of chronic kidney disease on the survival of patient with acute myeloid leukemia/High Risk MDS.

Methods
A retrospective study of all AML & high risk MDS patients treated at AGMC, Ohio, USA during 2001-2010. After IRB approval of the project, patients’ charts were reviewed to gather information on demographics, diagnosis types/subtypes, glomerular filtration rate (GFR), treatment, and cytogenetics. Patients were classified as low-intermediate risk or high risk according to cytogenetic background using WHO criteria. Also according to GFR patients were classified to GFR <30, 30 - 60 and > 60. Overall survival (OS) rates were determined by Kaplan-Meier Survival Analysis. Prognostic factors were evaluated by Log Rank analysis.

Result
Out of 130 patients we were able to classify 99 patients (75%). Patient were grouped into 59 Pts with GFR>60, 37 Pts with GFR 30-60 and 3 Pts with GFR<30. Time to event survival analysis was done.

Conclusion
Glomerular filtration rate GFR is a major identified factor in patients survival who have acute myeloid leukemia AML/High Risk MDS, those patients with GFR 30-60 do better in term of survival, we don’t have any explanation for that, more data with high number of patients needed to elaborate on this issue.

Disclosures:
No relevant conflicts of interest to declare.
Increased 14-3-3ζ Expression In The Multidrug-Resistant Leukemia Cell Line HL-60/Vcr As Compared To HL-60 Cell Line Mediates Cell Growth and Apoptosis
Authors: Liang Rong , Chen Xiequn qun , Bai Qing xian , Wang Zhe , Yang Lan , Zhang Tao , Dong Bao xian , Gao Guang xun , Gu Hong tao , Zhang Liang 
Published: October 2019

Abstract

Objectives
Acute myeloid leukemia (AML) recurrence is largely a result of multidrug resistance (MDR). Because vincristine-resistant HL-60 cells (HL-60/VCR) express greater levels of 14-3-3¦Æ, which is associated with apoptosis and chemosensitivity in other cancers, this study sought to examine its role in AML chemosensitivity using HL-60 and HL-60/VCR cells.

Methods
The mRNA and protein expression of 14-3-3¦Æ, mdr1, Pgp, BCL-2 and MCL-1 were examined using semi-quantitative RT-PCR and Western blot analyses, respectively. The subcellular location of 14-3-3¦Æ protein in HL-60 and HL-60/VCR cells was determined using immunofluorescence and confocal microscopy. After siRNA-mediated silencing of 14-3-3¦Æ in HL-60 AND HL-60/VCR cells, cell growth and cell cycle progression were determined by direct counting and flow cytometry, respectively. The effect of 14-3-3¦Æ siRNA on topotecan (TPT)-induced apoptosis was evaluated using acridine orange/ethidium bromide and Annexin V staining as well as TUNEL analysis. NF-¦ÊB-DNA biding was also assessed using electrophoretic mobility shift assay.

Results
As compared to HL-60 cells, increased 14-3-3¦Æ mRNA and protein expression was observed in HL-60/VCR cells. In addition, increased mdr-1 mRNA as well as Pgp, Bcl-2, and Mcl-1 protein expression were observed in HL-60/VCR cells. In both HL-60 and HL-60/VCR cells, 14-3-3¦Æ was observed in the cytoplasm and nuclear compartments. 14-3-3¦Æ siRNA significantly reduced HL-60 and HL-60/VCR cell growth after 48 h and increased the proportion of cells in the G0/G1 phase. Moreover, 14-3-3¦Æ siRNA significantly increased the sensitivity of both HL-60 and HL-60/VCR cells to TPT possibly through inhibition of Bcl-2, Mcl-1 and Pgp protein expression. Conversely, increased Bad and Noxa protein expression was observed with 14-3-3¦Æ siRNA. NF-ĸB DNA binding was reduced with 14-3-3¦Æ siRNA.

Conclusions
Silencing of 14-3-3¦Æ increased the sensitivity of both sensitive and resistant HL-60 cells to TPT-induced apoptosis possibly through altering the expression of apoptosis-associated proteins, suggesting that it may be a potential target for MDR AML.

Disclosures:
No relevant conflicts of interest to declare.
Single Arm, Multi-Center, Phase II Study Of Clofarabine In Chinese Pediatric Patients With Refractory Or Relapsed Acute Lymphoblastic Leukemia
Authors: Zhang Leping , Du Xin , Li Yan , Cai Zhen , Yu Kang , Tan Fenlai , Fang Yi , Huang Xiaojun , Lu Jin 
Published: October 2019

Abstract

Background
Clofarabine is a second generation purine nucleoside which inhibits DNA polymerase alpha and ribonucleotide reductase, leading to the depletion of intracellular deoxynucleotide triphosphate pools, disruption of mitochondrial function and apoptosis. A phase II study was conducted to evaluate the safety and efficacy of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia (ALL) in China.

Method
Patients aged 1-21 years with histologically confirmed, relapsed and/or refractory ALL were eligible. Clofarabine was administered intravenously for 5 days at 52 mg/m2/d during induction and consolidation. The primary end point was overall remission rate (ORR; complete remission [CR] plus CR with incomplete counts [CRi]). Blood samples were obtained from patients who agreed to blood drawing for pharmacokinetic determinations.

Results
A total of 44 patients were treated in this study, in which 43 were evaluable for response. The median age was 13 years (range: 5 to 22 years), and the majority were B cell-ALL (75%, 33/44). The overall remission rate was 44.2% (19/43), including two complete remissions (CR), and 17 CRis. 39 patients had progressive disease at cut-off time, the overall median remission duration was 2.9 months, and the median remission duration was 3.4 months for patients achieved CR or CRi. Seven CR/CRi patients had chance to got HSCT after clofarabine treatment. Subgroup analysis showed that patients younger than 14 years and with B cell-ALL had a higher ORR than patients older than 14 years and with T cell-ALL, and the difference were statistically significant (age < 14 years vs. age ≥14 years: 60.9% vs. 25%, p =0.0308; B cell-ALL vs. T cell-ALL: 57.6% vs. 0, p=0.002). The most common (≥10%) adverse reactions (ADR) were hematological toxicity, gastrointestinal reaction, and abnormal liver function, and the most common grade 3/4 non-hematologic ADRs was ALT elevation (13.6%). PK analysis demonstrated that after multiple administrations the mean elimination half-life of clofarabine was 6.43 h, and the Tmax was around 2 h. The mean Cmax and exposure to clofarabine over the dosing period (AUC 0-24) achieved 581 ug/L and 2602.56 ug/L, respectively. It seems that there is no significant difference of PK profiles between Chinese and Caucasian patients.

Conclusion
Single clofarabine treatment is effective in Chinese pediatric patients with multiple relapsed or refractory ALL with acceptable safety profiles.

Disclosures:
No relevant conflicts of interest to declare.
Pegylated Asparaginase In Combination With Vincristine,Daunorubicin and Prednisone For Remission Induction In Adult Acute Lymphoblastic Leukaemia
Authors: Wei Na , Fu Li , Wang Jingshi , Wang Zhao 
Published: October 2019

Abstract
In contrast to that in children, the use of pegylated asparaginase in adult is very limited. We accept twenty-four newly diagnosed adult acute lymphoblastic leukemia (ALL) patients. Use pegylated asparaginase in combination with vincristine,daunorubicin and prednisone for remission induction. Pegylated asparaginase (Heng Rui Pharmaceuticals) administered at a dose of 2000 IU/m2 (maximum dose 3750 IU) intramuscular on day 10, 24. The aim was to observe complete response (CR) rate and side effect of the regimen. The overall CR rate was 91.67% (22/24), including 19 patients who were in CR after phase 1 of induction. 1 patient failed to achieve CR, and died of septicemia on day 24 of induction therapy. 1 Ph+ ALL patient got CR after Imatinib added. Grade 3 or 4 hematological adverse effects were seen in 100% patients. Most non-hematological adverse effects were grade 1or 2, including vomiting and nausea (87.5%), infection (66.7%), liver disfunction (50%), diarrhea (12.5) and pancreatitis (4.1%). No allergic reactions were observed. The level of fibrinogen and AT III descended in all patients, including 7 patients fibrinogen less than 1.0g/L, 14 patients AT III less than 50%. But no patient developed evidence of bleeding or thrombosis. This regimen got a satisfactory CR rate in adult ALL and was safe with few grade 3/4 side effects. Pegylated asparaginase was well tolerated, no allergic reactions evidence of bleeding or thrombosis was observed.

Disclosures:
No relevant conflicts of interest to declare.
Overcoming Drug Resistance Of FLT3-ITD By SAR302503
Authors: Kesarwani Meenu , Huber Erika , Azam Mohammad 
Published: October 2019

Abstract
A recent discovery of secondary mutations in the kinase domain of Fms-like tyrosine kinase 3 (FLT3) targeted by kinase inhibitor AC220 (quizartinib) established it as a relevant target in acute myeloid leukemia (AML). However, at the same time these observations suggest to identify next-generation inhibitors to target the resistant variants of FLT3. Here we show that SAR302503, a JAK2/FLT3 inhibitor in phase III trial for the treatment of polycythemia vera (PV) and myelofibrosis (MF), can potently inhibit FLT3-ITD variants that confer resistance to AC220. Interestingly, In vitro drug selection against SAR302503 at Cmax value (3 uM) failed to develop resistant clones suggesting it will be more effective in preventing the emergence of resistant clones. Structural modeling suggests that SAR302503 is a type I inhibitor that binds to ATP site in a DFG-in conformation. Altogether our data supports for clinical evaluation of SAR302503 for naïve and resistant variants of FLT3-ITD in AML patients to manage clinical resistance.

Disclosures:
No relevant conflicts of interest to declare.
Treatment With Leukapheresis In Patients Diagnosed With Hyperleukocytic Acute Myeloid Leukemia
Authors: Martínez-Cuadrón David , Montesinos Pau , Moscardo Federico , Lopez Lineth , Martin Guillermo , Solves Pilar , Boluda Blanca , Pérez-Sirvent Mariluz , Vera Belen , Navarro Ines , Alonso Carmen M , Martinez Jesus , López-Chulia Francisca , Sanz Jaime , Carpio Nelly , Rodríguez-Veiga Rebeca , Iacoboni Gloria , Sanz Guillermo , Sanz Miguel 
Published: October 2019

Abstract

Background
Patients with hyperleukocytic acute myeloid leukemia (AML) have a high mortality rate during induction treatment. This mortality is mainly due to bleeding complications, tumor lysis syndrome and symptoms of hyperleukocitosis. Although there is no clear evidence of benefit, leukapheresis is indicated to reduce the number of leukocytes (WBC) in peripheral blood and prevent or relieve leukostasis symptoms before starting cytotoxic therapy.

Objetives
Analyze the characteristics of a series of patients with hyperleukocytic AML who started induction treatment and assess the outcome depending on whether leukapheresis was performed or not.

Methods
All adult patients with hyperleukocytic AML (WBC> 95 x 109 / L) who received induction therapy in the Hospital La Fe between 1979 and 2012 were included. The leukapheresis was indicated according to physician discretion. The characteristics and mortality of both groups, patients who underwent leukapheresis and non-leukapheresis, were compared. Then a “matched-paired analysis” was performed according to ECOG, WBC and coagulopathy in a 2:1 ratio to compare results from two homogeneous cohorts.

Results
One hundred and forty patients diagnosed with hyperleukocytic AML received induction therapy, 18 of them underwent leukapheresis. Patients who underwent leukapheresis compared with non-leukapheresis showed a median age of 55 years (16-71) vs 58 (14-75) and WBC at diagnosis of 198 ´ 109 / L (101-620) vs 141 (97-375), respectively. The leukapheresis group had a worse ECOG (p = 0.03), more leukocytes (p = .003), more coagulopathy (p = .03), more leukostasis symptoms (p <.001) and more mortality at 7 days (p = .02). From the “matched-paired analysis”, 2 cohorts were obtained, whose characteristics are shown in Table 1. After comparing the group of leukapheresis and non-leukapheresis (n = 36), there were no significant differences between them, including leukocyte count, ECOG, coagulopathy and leukostasis. There were also no significant differences in mortality at 7, 14, 21 and 28 days (p = .60, p = .99, p = .92, p = .99, respectively).

Conclusions
Patients diagnosed with hyperleukocytic AML who underwent leukapheresis showed more leukocytes, leukostasis and coagulopathy. After analizying two comparable groups, leukapheresis failed to reduce mortality.

Disclosures:
No relevant conflicts of interest to declare.
STAT3 Predicts Poor Outcome In Patients With Advanced Diffuse Large B Cell Lymphoma
Authors: Feng Ru , Wei Xiaolei , Xu Meng , Huang Fen , Wei Yongqiang , Zhao Tong , Ye B. Hilda 
Published: October 2019

Abstract

Objective
To explore the expression and prognosis of STAT3 in Chinese patients with diffuse large B-cell lymphoma (DLBCL).

Methods
The expression of STAT3 was examined by the immunohistochemistry (IHC) method.120 patients with de novo DLBCL were reviewed retrospectively.

Results
Among the 120 patients, the ratio of male to female was 1.26:1, 47.5% of them were Non-GCB and 52.5% were GCB-DLBCL. The expression of STAT3 was observed in 50 of 120 cases (41.7%) and more frequent in the non-germinal center B cell-like (Non-GCB) DLBCL than that in the GCB subtype. The prognosis analysis showed that age, B symptom, bone marrow involvement, number of extranodal involvement, LDH, cell of origin and IPI related with prognosis, but not the expression of STAT3. However, in patients with advanced diffuse large B cell lymphoma, the expression of STAT3 was a poor prognostic factor.

Conclusion
STAT3 is expressed predominantly in Non-GCB DLBCL. The expression of STAT3 correlates poor outcome in patients with advanced diffuse large B cell lymphoma.

Disclosures:
No relevant conflicts of interest to declare.
A Therapeutic Vaccine In Adult T-Cell Leukemia Patients With Autologous Dendritic Cells Pulsed With Peptides Corresponding To Tax-Specific Cytotoxic T Lymphocyte Epitopes
Authors: Iino Tadafumi , Suehiro Youko , Hasegawa Atsuhiko , Watanabe Nobukazu , Tanosaki Ryuji , Utsunomiya Atae , Matsuoka Masao , Teshima Takanori , Akashi Koichi , Uike Naokuni , Okamura Jun , Kannagi Mari 
Published: October 2019

Abstract
Adult T-cell leukemia (ATL) is an aggressive peripheral T-cell neoplasm with extremely poor prognosis. It typically develops due to long-term infection with human T-cell leukemia virus type 1 (HTLV-1). Among HTLV-1 antigens, the viral regulatory protein Tax is widely recognized as a target of cytotoxic T lymphocytes (CTLs), and Tax-specific CTLs are often activated in ATL patients following hematopoietic stem cell transplantation (HSCT). This strongly suggests the presence of Tax expression in vivo and potential contributions of CTL to GVL effects. Based on these findings, we developed an anti-ATL therapeutic vaccine consisting of autologous dendritic cells (DC) pulsed with Tax peptides corresponding to the major epitopes of Tax-specific CTL that were previously identified from human leukocyte antigen (HLA)-A2, A24 or A11-possessing ATL patients post-HSCT (Cancer Res. 2004, J Virol. 2005). In preliminary experiments, the DC induced with a conventional method showed matured phenotype and produced interleukin (IL)-12 in two of three ATL patients tested.
After approval by the institutional ethics committees, we conducted a phase I clinical trial of anti-ATL immunotherapy for pretreated ATL patients in stable condition in order to evaluate whether HTLV-1 Tax targeting immunotherapy is safe and feasible. The vaccine protocol consists of three subcutaneous injections of peptide-pulsed DC at 2-week intervals in a total 8-week observation period to assess adverse events. Three acute-type patients enrolled and completed the course of the study. Modest clinical symptoms, such as injection site reaction, fever, and skin damage, were observed in all cases. DC vaccine-related toxicities were grade 1 or 2 and were considered relatively mild, and non-hematological toxicity was acceptable. In addition, significant reduction in sIL-2R levels were observed at least in one patient, and the HTLV-1 proviral loads were maintained below 60 copies /1000 PBMCs during the monitored period after administration of DC in the all patients. Enhanced proliferative responses of Tax-specific CTLs were also observed in vitro after therapy. Clinical effects, as evaluated by RECIST, were partial remission in two patients and stable disease in one patient. Durable remissions and improvements in performance status were observed in all three patients without the requirement for new treatment for 4-10 months after treatment with Tax-targeted DC vaccination. These results indicate that Tax-specific DC vaccination is safe and well tolerated, and may be promising as a new therapeutic strategy for ATL patients.

Disclosures:
No relevant conflicts of interest to declare.
Combination Of Arsenic and Interferon-a Inhibits Expression Of KSHV Latent Transcripts and Synergistically Improves Survival Of Mice With Primary Effusion Lymphomas
Authors: El Hajj Hiba , Ali Jihane , Ghantous Akram , Hodroj Dana , Daher Ahmad , Daher Ahmad , Zibara Kazem , Journo Chloé , Otrock Zaher K. , Zaatari Ghazi , Mahieux Renaud , El Sabban Marwan , Merhi Raghida Abou , Bazarbachi Ali 
Published: October 2019

Abstract

Background
Kaposi sarcoma-associated herpesvirus (KSHV) is the etiologic agent of primary effusion lymphomas (PEL). PEL cell lines infected with KSHV, but negative for Epstein-Barr virus have a tumorigenic potential in non-obese diabetic/severe combined immunodeficient mice and result in efficient engraftment and formation of malignant ascites with notable abdominal distension, consistent with the clinical manifestations of PEL in humans.

Methodology/Principal findings
Using this preclinical mouse model, we demonstrate that the combination of arsenic trioxide and interferon-alpha (IFN) inhibits proliferation, induces apoptosis and downregulates the latent viral transcripts LANA-1, v-FLIP and v-Cyc in PEL cells derived from malignant ascites. Furthermore, this combination decreases the peritoneal volume and synergistically increases survival of PEL mice.

Conclusion/Significance
These results provide a promising rationale for the therapeutic use of arsenic/IFN in PEL patients.

Disclosures:
No relevant conflicts of interest to declare.