bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression Level of Granulocyte-Colony Stimulating Factor Receptor and Effect of Two Forms of G-CSF to in AML1/ETO+ Acute Myelogenous Leukemia.
Authors: Moon Heewon , Kim Tae Young , Min Hyun Chung , Oh Bo Ra , Yoon Sung Soo , Kim Byoung Kook , Cho Han Ik , Lee D.S. ,   AML/MDS Working Party
Published: October 2019

Abstract
In our previous study, we have revealed that cases showing remission after treatment with G-CSF mostly had leukemia with AML1/ETO rearrangement and suggested that this finding might be explained by higher expression of G-CSF receptor (G-CSFR) in AML1/ETO+ cells than in AML1/ETO− cells. To confirm the relationship between AML1/ETO fusion gene and G-CSFR expression, we applied small interfering RNAs (siRNAs) for efficient suppression of AML1/ETO gene expression and observed the change of G-CSFR expression. Moreover, we investigated the effect of most commonly used two forms of G-CSF (glycosylated lenograstim and nonglycosylated filgrastim) on AML1/ETO positive leuekemic cells and other cell lines. Kasumi-1 cells (AML with AML1/ETO gene rearrangement) were transfected with AML1/ETO specific siRNAs (siAM, siAGF1) and isolated for investigation of G-CSFR gene expression using real time PCR. The proliferation effect of two different forms of G-CSF on was evaluated using Cell-Titer 96® Non-Radioactive Cell Proliferation Assay (Promega Co., Madison, WI, USA). G-CSFR expression was decreased in AML1/ETO gene suppressed cells by both siRNAs. The levels of G-CSFR mRNA were 27% of untreated control with siAGF, 23% with siAM at 16 hours after trasnfection. Both forms of G-CSF significantly stimulated the proliferation of Kasumi-1 cells compared to control cells without G-CSF treatment (40–80% of control increased). The degree of proliferation was similar with different forms of G-CSF (filgrastim and lenograstim) at different concentrations (10, 50 and 100 ng/mL). In K562 cells(chronic myelogenous leukemia), proliferation was increased only at 50ng/ml filgrastim after 72 hours. The CTV-1 cells (AML without AML1/ETO gene rearrangement) showed slightly increased proliferation activities only after 72 hours of lenograstim treatment. In U266 cells (Multiple myeloma) showed no significant response on proliferation with G-CSF. In conclusion, our study revealed that AML1/ETO rearrangement increased the G-CSFR expression and G-CSF had proliferation effect on AML1/ETO-positive cells. Thus, the effect of G-CSF should be considered when we decide the remission or treatment plan, especially for AML1/ETO+ AML with high G-CSFR expression.
Influence of High Expression of p73 and p53 Proteins on Clinical Outcome in Acute Myeloid Leukemia Patients.
Authors: Pluta Agnieszka , Smolewski Piotr , Wierzbowska Agnieszka , Cebula Barbara , Jamroziak Krzysztof , Robak Tadeusz 
Published: October 2019

Abstract
Background: Prognostic significance of apoptosis-regulating proteins, especially p73, is not clearly determined in acute myeloid leukemia (AML). The p73 protein is a member of p53 family implicated in the regulation of cell cycle, apoptosis and development. Overexpression of p73 protein, with prevalence of short TAp73 isoforms, has recently been described in patients with AML.
Aims: The main objective of this study was to verify whether expression of p73 and p53 proteins has a prognostic impact on response to induction chemotherapy and overall survival (OS) of adult patients with AML. Additionally, we aimed to correlate the expression of p73 and p53 proteins with spontaneous apoptosis of leukemic cells.
Material and Methods: Intracellular expression of p73 protein in leukemic blasts isolated from bone marrow or peripheral blood was examined in 73 AML patients (59 de novo, 14 refractory/relapsed) of median age 54 years (range 28–78 years). In parallel, analysis of cell cycle in leukemic blasts was performed to assess the subG1 fraction as a marker of spontaneous apoptosis. The control constituted leukemic cells incubated with isotype antibodies. All measurements were performed using multi-colour flow cytometry. Protein expression was expressed by both percentage of positive cells and mean fluorescence intensity.
Results: Fifty six patients received intensive induction chemotherapy. Twenty four (43%) patients achieved complete response (CR), 26 (46%) patients did not respond and 6 (11%) patients died in the early post-induction period. The median time of follow up reached 5.6 months (range 0.1–99 months). High expression of p73 showed a trend towards probability of CR achievement after induction regimen (p=0.08). Higher expression of p53 did not correlate with response to the treatment (p=0.28). In univariate analysis we found significantly better OS in patients less than 60 years old, with good or intermediate risk of kariotype and treated with intensive chemotherapy (p=0.00001; p=0.04; p=0.00001, respectively). Probability of better OS in AML patients with high p73 and p53 protein expression was p=0.1 and p=0.95, respectively. Simultaneous high expression of both p73 and p53 proteins on AML cell showed a trend toward longer OS (p=0.09). Moreover, a strong trend to better OS was observed in patients with high subG1 fraction. Importantly, high subG1 fraction correlated with high expression of p53 but not with p73 protein expression (p=0.03; p=0.15, respectively).
Conclusions: These data indicate that p73 protein may be implicated in apoptosis of AML in response to chemotherapy, especially when p53 pathway is abrogated. Further studies are needed to establish exact role of p73 and p53 proteins in this process and its influence on OS of AML patients.
A Rapid Assay of Cytosine Arabinoside Uptake and Metabolism by Acute Myeloid Leukaemic Cells Using a Bioluminescent Bacterial Biosensor.
Authors: Smith Graham , Alloush Habib , Smith Margaret A. , Hill Philip J. , Salisbury Vyvian 
Published: October 2019

Abstract
We have already reported the construction and evaluation of a self-bioluminescent reporter strain of E. coli with high sensititivity to the nucleoside analogue cytosine arabinoside (Ara-C) the mainstay of treatment in patients with Acute Myeloid Leukaemia (Blood, 106 (11), Abstr. 2473; 695a). This rapid assay, which uses a bioluminescent biosensor to measure intracellular levels of Ara-C and its active metabolite Ara-CTP, has been utilised in leukaemic cell lines KG1a (FAB type M0) which is sensitive to Ara-C and THP-1 (FAB type M5) which is partially insensitive to Ara-C due to over expression of cytidine deaminase (cdd). It has also been used in primary cultures of AML cells from six patients with M0 (n=1), M2 (n=2), M3 (n=1) and M4 (n=2). Intracellular concentrations of Ara-C as low as 0.05 μM can be detected by an increase in light output from the bacterial biosensor. The technology is suitable for the quantitation of response to clinical Ara-C doses (between 25–100μM) in less than 8 hours. Results from the KG1a cell line with known sensitivity to Ara-C showed correlation between the rapid assay and a 3 day cytotoxicity test of Ara-C sensitivity. Preliminary tests with the six clinical marrow samples showed 100% concordance with clinical outcome within eight hours of commencing the assay (vide infra: Table 1). In newly diagnosed AML patients, only 70% are sensitive to Ara-C therapy. Interestingly, in our hands, the M3 patient was Ara-C insensitive despite the fact that, most commonly, M3 patients do not express p-glycoprotein and therefore do not require Ara-C. Our small cohort of patients were disproportionately insensitive to Ara-C and therefore had a poor outcome overall. This assay system is potentially suitable for prescreening AML samples prior to commencement of Ara-C containing chemotherapy regimens. It may also give information on relative Ara-C sensitivity thus permitting dose adjustment and prevention of unnecessary toxicity to other organs. The assay could be repeated at relapse to document clonal evolution and decide whether Ara-C can be used to achieve a second remission. Work is currently underway with an industrial partner to look at commercialisation of this assay.
TABLE 1: Correlation between light output and clinical response in six patients with primary AML Patient Diagnosis Clinical Outcome Differential Light Output: cytotoxicity test Bioluminescent Assay: Ara-C sensitivity 1 M0 No response 5% no 2 M2 No Response 84% no 3 M2 No Response 79% no 4 M3 Remission Death 91% no 5 M4 Complete Response 99% yes 6 M4 No Response 62% no
Preliminary Study on Effects of Marsdenia Tenacissima Injection on NB4 Cells.
Authors: Li Dong , OuYang Jian , Li Cuiping , Chen Junhao 
Published: October 2019

Abstract
Purpose To study the effect of Marsdenia tenacissima injection on NB4 leukemia cells and its mechanisms.
Methods After treated with Marsdenia tenacissima, viability of NB4 leukemia cells were determined by trypan blue assay. Cell cycle was assessed by FACS. Cell differentiation were determined by cell morphology, cell surface differentiation antigen and NBT reduction test. Cell cycle and apoptosis associated proteins were measured by western blot.
Results Marsdenia tenacissima inhibits the growth of leukemia cells in a dose and time dependent manner. Marsdenia tenacissima induces G0/G1 phase arrest of NB4 cells, accompanied by P21 up-regulation. Marsdenia tenacissima did not change the protein level of PARP and p27. Marsdenia tenacissima could increase the expression of CD11b and percent of NBT positive cells, induces differentiation of NB4 cells.
Conclusion Marsdenia tenacissima could inhibit the proliferation of NB4 cells through inducing cell cycle arrest and cell differentiation.
Prognostic Value of Immunophenotyping in Elderly Patients with Acute Myeloid Leukemia: A Single Institution Experience.
Authors: Plesa Claudiu , Chelghoum Youcef , Plesa Adriana , Elhamri Mohamed , Tigaud Isabelle , Michallet Mauricette , Dumontet Charles , Thomas Xavier 
Published: October 2019

Abstract
The poor prognosis of elderly patients with acute myeloid leukemia (AML) raises the question about the benefit of intensive chemotherapy in these patients. The impact of initial characteristics on prognosis has previously been addressed in elderly paitents, but very few data are available regarding the prognostic value of immunophenotypic characteristics in this setting. We investigated the expression of the membrane antigens CD13, CD15, CD33, and CD34 by flow cytometry in elderly patients with newly diagnosed AML, and analyzed whether these parameters possessed clinical or prognostic relevance, in order to help physicians in their choice of therapy. Immunophenotyping was performed in 273 patients aged 60 years or more (median 69 years). CD13 was expressed in 73%, CD15 in 43%, CD33 in 64%, and CD34 in 66% of cases. Complete remission was obtained in 157 cases (58%). The median overall survival was 8.1 months with a 3-year survival rate of 14%. Three risk groups were defined based on CD34 and CD33 antigen expression: Poor risk in patients with CD34+ CD33+ or CD34− CD33− disease, intermediate risk in patients with CD34+ CD33− disease, and favorable risk in patients CD34− CD33+ disease. Immunophenotype was, after cytogenetics, the most significant prognostic factor in terms of survival in a multivariate analysis (p = 0.03 and p < 0.0001 respectively). When combining immunophenotypic and cytogenetic parameters, patients were classified into four prognostic groups: Group A (3-year survival: 33%) including favorable and normal karyotypes with a favorable immunophenotype; Group B (3-year survival: 28%) including normal karyotypes with an intermediate immunophenotype; Group C (3-year survival: 8%) including intermediate or normal karyotypes with an unfavorable immunophenotype; and Group D (3-year survival: 2%) including all unfavorable cytogenetics. Immunophenotypic characteristics appeared to be a major prognostic factor in this patient population. Using two simple parameters assessed at time of diagnosis, we devised a prognostic system of immediate clinical utility for prognostic stratification and risk-adapted therapeutic choices.
Efficacy of Mitoxantrone and Etoposide in Patients with Acute Myeloid Leukemia Refractory to Initial Standard Induction Therapy.
Authors: Sehgal Rajesh , McHayleh Wassim , Natale James , Raptis Anastasios , Agha Mounzer , Redner Robert L. , Richard Gene , Welsh Ann , Foon Kenneth A. , Boyiadzis Michael 
Published: October 2019

Abstract
The most effective reinduction regimen for acute myeloid leukemia (AML) patients who do not achieve complete remission (CR) after one cycle of cytarabine combined with an anthracycline is not well established. In an effort to search for new synergistic and non-cross resistant antileukemic regimens different chemotherapeutic combinations have been investigated in refractory AML patients. Multiple regimens including high dose cytarabine, anthracyclines, fludarabine and etoposide have been used with CR rates up to 40%. Mitoxantrone and etoposide have activity in AML as induction agents but their role in reinduction in patients not responding to first line therapy has not been fully established. In the current retrospective study we evaluated the efficacy and toxicity of mitoxantrone and etoposide in AML patients treated at our institution who did not respond to first induction therapy with cytarabine and an anthracycline. A total of fifty seven AML patients were treated with mitoxantrone and etoposide (mean age 55 years, range 18–75 years). Twenty four patients were treated with mitoxantrone 10 mg/m2/d and etoposide 100 mg/m2/d both administered intravenously, days 1 to 5 (regimen 5+5) and thirty three patients were treated with mitoxantrone 10 mg/m2/d administered intravenously days 1 to 3 and etoposide 100 mg/m2/d administered intravenously, days 1 to 5 (regimen 3+5). Twenty six of fifty seven patients (46%) achieved CR. CR was achieved in 38% of patients (9/24) treated with the 5+5 regimen and 52% of patients (17/33) treated with the 3+5 regimen. Mean blast percentage before treatment with mitoxantrone and etoposide was 25% in patients who achieved CR vs 40% in patients who did not achieve CR (p < 0.03). Grade 3/4 hepatic toxicities were seen in 5% (3/57) of patients and there were no grade 3 or 4 renal toxicities. The median duration of neutropenia in patients achieving CR was 29 days after reinduction. 10% (6/57) of the patients died from infectious complications. Cytogenetic analyses were performed prior to first-line therapy in all patients. Patients with favorable cytogenetics treated with etoposide and mitoxantorne had 100% CR (3/3), patients with standard cytogenetics had 58% CR (19/33) and patients with unfavorable cytogenetics had 19% CR (4/21). Overall CR was achieved in 61% (22/36) of patients with favorable and standard cytogenetics. Our data suggest that the combination of etoposide and mitoxantorne is an active and well tolerated regimen, especially in patients with favorable and standard cytogenetics, and warrants further studies in prospective trials.
Combination Methyltransferase and Histone Deacetylase Inhibition in Elderly Patients with Secondary Acute Myelogenous Leukemia.
Authors: Thatikonda Chandanda , Rossetti James M. , Shadduck Richard K. , Lister John 
Published: October 2019

Abstract
Background: Secondary acute myelogenous leukemia (AML) carries a poor prognosis when compared to de novo AML. Therapeutic options are typically limited as patients are often elderly with comorbidities that preclude intensive chemotherapy. Moreover, resistance to therapy is common. Studies have shown that methyltransferase inhibitors (MTI) have activity in myeloid malignancy. It is not known if addition of histone deacetylase (HDAC) inhibitors improves or prolongs the activity of MTI. We present our experience of 3 elderly patients with secondary AML treated with MTI (azacitidine or decitabine) in combination with an HDAC inhibitor (vorinostat).
Methods: Patients include 2 males and 1 female, ages 78 yrs, 82 yrs and 71 yrs. All were initially diagnosed with high-grade myelodysplastic syndrome (MDS), which transformed to CD34+ secondary AML at 33, 14 and 4 months from diagnosis of MDS, respectively. One patient had trisomy 8. Patients received 8, 3 and 4 cycles of MTI before leukemic transformation, respectively. At transformation, one patient failed standard induction therapy and 1 patient failed arsenic trioxide. Both of these patients were then placed back on MTI as maintenance therapy. Vorinostat was added at a dosage of 400 mg daily at MTI cycles 8, 3 and 1 post transformation, respectively. The number of cycles of combination therapy was 6, 9 and 4. Gastrointestinal intolerance was an issue in 2 of these patients: nausea (n=2), diarrhea (n=2), vomiting (n=1) and loss of appetite (n=1). Dose reduction to 100mg in one patient and 300 mg in another resulted in some symptomatic relief. The addition of 5-HT3 antagonists or low dose prednisone allowed dose escalation. One patient had 50% reduction in marrow blasts, 1 had near clearance of the peripheral blasts and 1 had a transient minor platelet response. All 3 patients are alive at 14, 10 and 9 months post transformation (6, 8 and 7 months after addition of vorinostat) with no disease progression, respectively.
Conclusion: The combination of MTI and HDAC could be an option in elderly patients with secondary AML without increasing morbidity and mortality. Treatment appears well tolerated when premedication with 5-HT3 antagonists is employed. As the treatment options are limited in high-risk elderly patients with secondary AML, larger studies are needed to investigate the utility of this combination.
Bortezomib (Velcade™) Observational Study in China - Efficacy and Safety of Bortezomib Based Regimen in 223 Relapsed or Refractory Multiple Myeloma Patients.
Authors: Shen Zhi-xiang 
Published: October 2019

Abstract
Introduction: Multiple myeloma (MM) is a plasma-cell malignancy with approximately three years’ median survival. Patients usually relapse or become refractory to existing treatments. Clinical studies have confirmed that bortezomib is an effective agent for relapsed MM patients and has potent synergy with other chemotherapeutic agents, which provides a new clinical regimen that may improve response. In this observational study, we intend to observe the safety/tolerability and efficacy of bortezomib-based regimens in Chinese patients with relapsed/refractory MM.
Methods: This was a multicenter, open-label, phase IV observational study for patients with relapsed or refractory MM. Bortezomib (0.7 to 1.6 mg/m2 i.v.) was given on days 1, 4, 8, and 11 of a 21-day cycle, for a maximum of 8 cycles, combined with other agents, mainly of dexamethasone addition. If pyretic neutropenia, grade 4 hematologic adverse events (AEs), or grade ≥3 non-hematologic AEs developed, bortezomib treatment was temporarily discontinued and re-administered at 75% of the initial dosage after remittance of the AEs. Responses were classified mainly by European Group for Blood and Marrow Transplantation criteria (EBMT).
Results: Between Mar 2006 and May 2007, 223 patients with MM were enrolled at 31 medical centers. Median age was 58 years (range 35–82), 96% of patients were in stage II/III, and the most common subtype was IgG (46%). Patients had received various prior therapies such as VAD (29% of patients), VBMCP (M2) (16%), and thalidomide combinations (15%). There were 198 patients evaluable for response, of whom 54 (27%) achieved a complete response (CR), 99 (50%) achieved a partial response (PR), 20 (10%) had minimal response (MR), 16 (8%) had stable disease (SD), and the other 9 (5%) had progressive disease (PD). Patients who received 4 or more cycles of bortezomib achieved a higher CR rate (56%) compared with patients who received fewer cycles (partly due to adverse event). Rapid responses were seen with the median time to response being 1 cycle (range 1–5). Common predictive factors including age, isotype, number of previous therapies, concentration of C-reactive protein, or beta2-microglobulin had no significant influence on treatment response. The incidence of adverse events (AEs) was 54%, including 18% of patients with hematologic AEs (33% of them grade 3–4), 27% with gastrointestinal AEs (50% of them grade 3–4), and 20% with peripheral neuropathy (40% of them grade 3–4). Serious AEs occurred in 25 (11%) patients. Most AEs were predictable and manageable.
Conclusions: These data demonstrate that a bortezomib-based regimen is a promising regimen with high response rate and is well tolerated in most relapsed and refractory MM patients. Additional clinical trials and long-term follow-up on Chinese patients are warranted.
Oral Acyclovir Is an Effective in Decreasing the Incidence of Bortezomib Associated Herpes Zoster in Patients with Multiple Myeloma.
Authors: DePaolo Dawn , Miller Kena C. , Whitworth Amy , Mohr Alice , Mashtare Terry L. , Wilding Gregory , Ailawadhi Sikander , Padmanabhan Swaminathan , Chanan-Khan Asher A. 
Published: October 2019

Abstract
Introduction: Bortezomib, a proteasome inhibitor is an effective antimyeloma therapy. We recently reported that multiple myeloma patients treated with bortezomib or bortezomib based regimen resulted in a higher incidence of herpes zoster (HZ). The exact etiology of this side effect remains unknown though our investigation demonstrated prolonged lymphopenia among patients treated with bortezomib. The high incidence of HZ among bortezomib treated patients prompted to prospectively investigate the role of antiviral prophylaxis in this patient population. Here we report for the first time the efficacy of acyclovir as prophylaxis for bortezomib associated HZ.
Patients and Methods: We prospectively evaluated the impact of oral acyclovir (400mg PO twice daily for the duration of bortezomib therapy) on the incidence of HZ. All patients with multiple myeloma who were treated with bortezomib or bortezomib based regimens, and received prophylactic acyclovir were evaluable for this analysis. To compare the overall proportion of HZ among patients who received acyclovir prophylaxis and the historical control, Fisher exact test was used.
Results: A total of 51 consecutive patients (27 M and 24 F) received acyclovir as prophylaxis. The median age was 61 (range 40–81 years), with advance stage MM noted in 86% (n=44) patients. Among these 69% had previously untreated MM while 31% had relapsed or refractory disease. Single agent bortezomib was given to 11 patients and 40 patients received bortezomib in combination with other antimyeloma agents (such as thalidomide, pegylated liposomal doxorubicin, dexamethasone, cyclophosphamide and/or lenalidomide). The overall incidence of HZ was 0% among patients receiving the acyclovir prophylaxis vs. 13% in the historical control. There was a significant difference in the overall proportion of HZ among patients who received acyclovir prophylaxis and the historical control (p = 0.0026).
Conclusion: This is the first report on the efficacy of acyclovir for the prevention of bortezomib associated HZ in MM patients. While bortezomib is an effective antimyeloma therapy, an important side effect with significant morbidity is reactivation of HZ. Here we demonstrate for the first time that this side effect can be effectively prevented by oral acyclovir. Our observation warrants further evaluation. Considering significant morbidity associated with HZ we recommend the routine use of prophylactic acyclovir (or other antiviral agents) for patients being treated with bortezomib or bortezomib-based therapies.